2,5-Inter-o-phenylene-3,4-dinor-6,9α-epoxy-6.beta.-5-iodo-PGF1 compounds

ABSTRACT

The present invention provides 2,5-inter-o-phenylene-3,4-dinor-6,9α-epoxy-6β-5-iodo-PGF 1  compounds. These compounds are intermediates for preparing 2,5-inter-o-phenylene-3,4-dinor-prostacyclin analogs, which are useful for pharmacological purposes, e.g., as antithrombotic agents.

DESCRIPTION CROSS REFERENCE TO RELATED APPLICATION

This application is a division of Ser. No. 062,443, filed 31 July 1979,now pending, which is a continuation-in-part of Ser. No. 962,845, filedNov. 22, 1978, now abandoned.

BACKGROUND OF THE INVENTION

The present invention relates to novel prostacyclin analogs andintermediates for their production. In particular, the present inventionrelates to prostacyclin intermediates useful in the production of2,5-inter-o-phenylene-3,4-dinor-prostacyclin analogs. Most particularlythe present invention provides2,5-inter-o-phenylene-3,4-dinor-6,9α-epoxy-6α-5-iodo-PGF₁ compounds. Thepreparation and use of the novel compounds described herein is describedin Appendix A.

SUMMARY OF THE INVENTION

The present invention particularly provides a prostacyclin intermediateof formula VIII ##STR1## wherein R₂₈ is --OR₁₀, --CH₂ OR₁₀, hydroxy,hydroxymethyl, or hydrogen, wherein R₁₀ is a blocking group;

wherein Y₁ is

(1) trans-CH═CH--,

(2) cis-CH═CH--,

(3) --CH₂ CH₂ --, or

(4) --C.tbd.C--,

wherein M₈ is α-R₅ :β-OR₁₀ or α-OR₁₀ :β-R₅, wherein R₅ is hydrogen ormethyl and R₁₀ is as defined above, or

α-R₅ :β-OH or α-OH:β-R₅, wherein R₅ is as defined above; wherein L₁ isα-R₃ :α-R₄, α-R₄ :β-R₃, or a mixture of α-R₃ :β-R₄ and α-R₄ :β-R₃,wherein R₃ and R₄ are hydrogen, methyl, or fluoro, being the same ordifferent, with the proviso that one of R₃ and R₄ is fluoro only whenthe other is hydrogen or fluoro;

wherein R₇ is

(1) --(CH₂)_(m) --CH₃, wherein m is an integer from one to 5, inclusive;

(2) phenoxy;

(3) phenoxy substituted by one, 2 or 3 chloro, fluoro, trifluoromethyl,alkyl of one to 3 carbon atoms, inclusive, or alkoxy of one to 3 carbonatoms, inclusive, with the proviso that not more than two substituentsare other than alkyl;

(4) phenyl;

(5) phenyl substituted by one, 2 or 3 chloro, fluoro, trifluoromethyl,alkyl of one to 3 carbon atoms, inclusive, or alkoxy of one to 3 carbonatoms, inclusive, with the proviso that not more than two substituentsare other than alkyl;

(6) phenylmethyl, phenylethyl, or phenylpropyl; or

(7) phenylmethyl, phenylethyl, or phenylpropyl substituted by one, 2 or3 chloro, fluoro, trifluoromethyl, alkyl of one to 3 carbon atoms,inclusive, alkoxy of one to 3 carbon atoms, inclusive, or with theproviso that not more than two substituents are other than alkyl; withthe proviso that R₇ is phenoxy or substituted phenoxy, only when R₃ andR₄ are hydrogen or methyl, being the same or different;

wherein R₁ is

(1) hydrogen;

(2) alkyl of one to 12 carbon atoms, inclusive;

(3) cycloalkyl of 3 to 10 carbon atoms, inclusive;

(4) aralkyl of 7 to 12 carbon atoms, inclusive;

(5) phenyl;

(6) phenyl substituted with one, 2 or 3 chloro or alkyl of one to 3carbon atoms;

(7) phenyl substituted in the para position by

(a) --NH--CO--R₂₅

(b) --CO--R₂₆

(c) --O--CO--R₂₇

(d) --CH═N--NH--CO--NH₂

wherein R₂₅ is methyl, phenyl, acetamidophenyl, benzamidophenyl, or--NH₂ ; R₂₆ is hydroxy, methyl, phenyl, --NH₂, or methoxy; and R₂₇ isphenyl or acetamidophenyl, inclusive, or a pharmacologically acceptablesalt thereof when R₁ is hydrogen.

The novel prostaglandin analogs prepared from the above intermediatesare useful for a variety of prostacyclin-like pharmacological purposes,particularly and especially as inhibitors of platelet aggregation invivo and in vitro. Thus, these prostacyclin analogs are useful for avariety of pharmacological and therapeutical purposes, e.g., asantithrombotic agents.

Those blocking groups within the scope of R₁₀ are any group whichreplaces a hydroxy hydrogen and is neither attacked nor is reactive tothe reagents used in the transformations used herein as an hydroxy isand which is subsequently replaceable with hydrogen in the preparationof the prostaglandin-type compounds. Several blocking groups are knownin the art, e.g., tetrahydropyranyl and substituted tetrahydropyranyl.See for reference E. J. Corey, Proceedings of the Robert A. WelchFoundation Conferences on Chemical Research, 12, Organic Synthesis, pgs.51-79 (1969). Those blocking groups which have been found usefulinclude:

a. tetrahydropyranyl;

b. tetrahydrofuranyl; and

c. a group of the formula

    --C(OR.sub.11)(R.sub.12)--CH(R.sub.13)(R.sub.14),

wherein R₁₁ is alkyl of one to 18 carbon atoms, inclusive, cycloalkyl of3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms,inclusive, phenyl or phenyl substituted with one to 3 alkyl of one to 4carbon atoms, inclusive, wherein R₁₂ and R₁₃ are alkyl of one to 4carbon atoms, inclusive, phenyl, phenyl substituted with one, 2, or 3alkyl of one to 4 carbon atoms, inclusive, or when R₁₂ and R₁₃ are takentogether --(CH₂)_(a) --or --(CH₂)_(b) --O--(CH₂)_(c), wherein a is 3, 4,or 5, or b is one, 2, or 3, and c is one, 2, or 3, with the proviso thatb plus c is 2, 3, or 4, with the further proviso that R₁₂ and R₁₃ may bethe same or different, and wherein R₁₄ is hydrogen or phenyl.

When the blocking group R₁₀ is tetrahydropyranyl, the tetrahydropyranylether derivative of any hydroxy moieties of the PG-type intermediatesherein is obtained by reaction of the hydroxy-containing compound with2,3-dihydropyran in an inert solvent, e.g., dichloromethane, in thepresence of an acid condensing agent such as p-toluenesulfonic acid orpyridine hydrochloride. The dihydropyran is used in large stoichiometricexcess, preferably 4 to 100 times the stoichiometric amount. Thereaction is normally complete in less than an hour at 20° to 50° C.

When the blocking group is tetrahydrofuranyl, 2,3-dihydrofuran is used,as described in the preceding paragraph, in place of the2,3-dihydropyran.

When the blocking group is of the formula

    --C(OR.sub.11)(R.sub.12)--CH(R.sub.13)(R.sub.14),

wherein R₁₁, R₁₂, R₁₃, and R₁₄ are as defined above, the appropriatereagent is a vinyl ether, e.g., isobutyl vinyl ether or any vinyl etherof the formula

    --C(OR.sub.11)(R.sub.12)═C(R.sub.13)(R.sub.14),

wherein R₁₁, R₁₂, R₁₃, and R₁₄ are as defined above; or an unsaturatedcyclic or heterocyclic compound, e.g., 1-cyclohexen-1-yl methyl ether,or 5,6-dihydro-4-methoxy-2H-pyran. See C. B. Reese, et al., Journal ofthe Chemical Society 89, 3366 (1967). The reaction conditions for suchvinyl ethers and unsaturated compounds are similar to those fordihydropyran above.

The blocking groups according to R₁₀ are removed by mild acidichydrolysis. For example, by reaction with (1) hydrochloric acid inmethanol; (2) a mixture of acetic acid- water, and tetrahydrofuran, or(3) aqueous citric acid aqueous phosphoric acid in tetrahydrofuran, attemperatures below 55° C., hydrolysis of the blocking groups isachieved.

APPENDIX A BACKGROUND OF THE INVENTION

This invention relates to novel structural and pharmacological analogsof prostacyclin (PGI₂), 5,6-dihydro-prostacyclin (PGI₁), and5,9α-epoxy-9-deoxy-PGF₁. In particular, the present invention relates toprostacyclin-type compounds wherein the alkylene chain between C-5 andC-2 is replaced by inter-o-phenylene and the epoxy oxygen is bonded tothe C-5 position.

Prostacyclin is a endogenously produced compound in mammalian species,being structurally and biosynthetically related to the prostaglandins(PG's). In particular, prostacyclin exhibits the structure and carbonatom numbering of formula I.

5,6-Dihydroprostacyclin exhibits the structure and carbon atom numberingof formula II. Similarly formula III provides the structure and carbonatom numbering of 5,9α-epoxy-9-deoxy-PGF₁ α.

As is apparent from inspection of formulas I, II, and III, prostacyclin,5,6-dihydroprostacyclin (i.e., PGI₁), and 5,9α-epoxy-9-deoxy-PGF₁ α beara structural relationship to PGF₂ α, which exhibits the structure andcarbon atom numbering of formula IV.

As is apparent by reference to formula IV, prostacyclin and5,6-dihydroprostacyclin may be trivially named as derivatives ofPGF-type compounds. Accordingly, prostacyclin is trivially named6,9α-epoxy-9-deoxy-(5Z)-5,6-didehydro-PGF₁. For description of thegeometric stereoisomerism employed above, see Blackwood et al., Journalof the American Chemical Society 90, 509 (1968). Further, for adescription of prostacyclin and its structural identification, seeJohnson, et al., Prostaglandins 12, 916 (1976).

For convenience, the novel prostacylcin analogs described herein will bereferred to by the trivial art-recognized system of nomenclaturedescribed by N. A. Nelson, Med. Chem. 17:911 (1974) and Johnson, R. A.,Prostaglandins 15:737 (1978). Accordingly, all of the novel prostacyclinderivatives herein will be named as 9-deoxy-PGF₁ -type compounds oralternatively as PGI₁ or PGI₂ derivatives.

In the formulas referred to above, as well as in formulas hereinafter,broken line attachments to any ring indicate substituents in "alpha" (α)configuration, i.e., below the plane of such ring. Heavy solid lineattachments to any ring indicate substituents in "beta" (β)configuration, i.e., above the plane of such ring. The use of wavy linesherein will represent attachment of substituents in either the alpha orbeta configuration or attachment in a mixture of alpha and betaconfigurations.

The side-chain hydroxy at C-15 in the above formulas is in S or Rconfiguration, as determined by the Cahn-Ingold-Prelog sequence rules.See J. Chem. Ed. 41:16 (1964). See also Nature 212, 38 (1966) fordiscussion of the stereochemistry of the prostaglandins, whichdiscussion applies to the novel prostacyclin analogs herein. Further,the carboxy-terminated side chain is attached to the heterocyclic ringof PGI₁ in either the alpha or beta configuration which by the aboveconvention represents the (6R) or (6S) configuration, respectively.Expressions such as C-5, C-15, and the like, refer to the carbon atom inthe prostaglandin or prostacyclin analog which is in the positioncorresponding to the position of the same number in PGF₂α orprostacyclin, as enumerated above.

Molecules of 5,9α-epoxy-9-deoxy-PGF₁α, PGI₁, PGI₂, and the novel,asymmetric prostacyclin analogs each have several centers of asymmetry,and can exist in racemic (optically inactive) form and in either of thetwo enantiomeric (optically active) forms, i.e., the dextrorotatory andlevorotatory forms. As drawn, the formula for PGI₂ corresponds to thatendogenously produced in mammalian tissues. In particular, refer to thestereoconfiguration at C-8 (alpha), C-9 (alpha), C-11 (alpha), and C-12(beta) of endogenously-produced prostacyclin.

For convenience hereinafter, use of the term prostaglandin ("PG") orprostacyclin ("PGI₂ ") will mean the optically active form of thatprostaglandin or prostacyclin thereby referred to with the same absoluteconfiguration as PGF₂α, obtained from mammalian tissues.

The term "prostaglandin-type" or "prostacyclin-type" (PG-type orPGI-type) product, as used herein, refers to any monocyclic or bicycliccyclopentane derivative herein which is useful for at least one of thesame pharmacological purposes as the prostaglandin or prostacyclin,respectively.

The formulas as drawn herein, which depict a prostaglandin-type orprostacyclin-type product or an intermediate useful in their respectivepreparations, each represent the particular stereoisomer of theprostaglandin-type or prostacyclin-type product which is of the samerelative stereochemical configuration as a corresponding prostaglandinor prostacyclin obtained from mammalian tissues, or the particularstereoisomer of the prostaglandin-type or prostacyclin-type products.

The term "prostaglandin analog" or "prostacyclin analog", as usedherein, represents that stereoisomer of a prostaglandin- orprostacyclin-type product which is of the same relative stereochemicalconfiguration as prostaglandins or prostacyclins obtained from mammaliantissues or a mixture comprising that stereoisomer and the enantiomerthereof. In particular, where a formula is used to depict aprostaglandin- or prostacyclin-type product herein, the term"prostaglandin analog" or "prostacyclin analog" refers to that compoundof that formula or a mixture comprising that compound and the enantiomerthereof.

Numerous therapeutic indications for prostacyclin have been established,based on its vasoactive and platelet antiaggregatory activities: (a)platelet preservation in vitro; (b) platelet preservation inhemodialysis; (c) maintenance of platelet numbers and function andprevention of deposition or aggregation during surgery involvingextracorporeal circulation; (d) prevention of CNS transient ischemicattacks or stroke or improvement of cerebral blood flow; (e) preventionor treatment of angina pectoris or myocardial infarction; (f) preventionof sudden cardiac death due to ventricular fibrillation; (g) preventionof postoperative venous thrombosis and thromboembolism; (h)pretransplantation perfusion of organs; (i) maintenance of patency intransplant or bypass vessels; (j) prevention of deposits which couldimpair function of artificial heart valves; (k) treatment ofmicroangiopathic hemolytic anemia; (l) treatment of peripheral vasculardisease; (m) treatment of pulmonary hypertension; and (n) treatment ofsystemic hypertension.

PRIOR ART

Interphenylene analogs of the prostaglandins are known to be useful forthe induction of prostaglandin-like pharmacological effects. Suchcompounds are described in U.S. Pat. No. 4,078,083, issued Mar. 7, 1978;U.S. Pat. No. 4,020,097, issued Apr. 26, 1977; and U.S. Pat. No.3,928,418, issued Dec. 23, 1975.

SUMMARY OF THE INVENTION

The present specification particularly provides:

a prostacyclin analog of formula V or VI; and

a prostacyclin intermediate of formula VII, VIII, or IX,

wherein Z₂ is cis-CH═CH-- or --CH₂ CH₂ --;

wherein R₂₈ is --OR₁₀, --CH₂ OR₁₀, hydroxy, hydroxymethyl, or hydrogen,wherein R₁₀ is a blocking group;

wherein R₈ is hydrogen, hydroxy, or hydroxymethyl;

wherein Y₁ is

(1) trans-CH═CH--,

(2) cis-CH═CH--,

(3) --CH₂ CH₂ --, or

(4) --C.tbd.C--,

wherein M₁ is α-R₅ :β-OH or α-OH:β-R₅, wherein R₅ is hydrogen or alkylwith one to 4 carbon atoms, inclusive,

wherein M₈ is α-R₅ :β-OR₁₀ or α-OR₁₀ :β-R₅, wherein R₅ and R₁₀ are asdefined above, or

α-R₅ :β-OH or α-OH:β-R₅, wherein R₅ is as defined above;

wherein L₁ is α-R₃ :β-R₄, α-R₄ :β-R₃, or a mixture of α-R₃ :β-R₄ andα-R₄ :β-R₃, wherein R₃ and R₄ are hydrogen, methyl, or fluoro, being thesame or different, with the proviso that one of R₃ and R₄ is fluoro onlywhen the other is hydrogen or fluoro;

wherein R₇ is

(1) --(CH₂)_(m) --CH₃, wherein m is an integer from one to 5, inclusive;

(2) phenoxy;

(3) phenoxy substituted by one, two or three chloro, fluoro,trifluoromethyl, alkyl of one to 3 carbon atoms, inclusive, or alkoxy ofone to 3 carbon atoms, inclusive, with the proviso that not more thantwo substituents are other than alkyl;

(4) phenyl;

(5) phenyl substituted by one, two or three chloro, fluoro,trifluoromethyl, alkyl of one to 3 carbon atoms, inclusive, or alkoxy ofone to 3 carbon atoms, inclusive, with the proviso that not more thantwo substituents are other than alkyl;

(6) phenylmethyl, phenylethyl, or phenylpropyl; or

(7) phenylmethyl, phenylethyl, or phenylpropyl substituted by one, twoor three chloro, fluoro, trifluoromethyl, alkyl of one to 3 carbonatoms, inclusive, or alkoxy of one to 3 carbon atoms, inclusive, withthe proviso that not more than two substituents are other than alkyl;with the proviso that R₇ is phenoxy or substituted phenoxy, only when R₃and R₄ are hydrogen or methyl, being the same or different;

wherein X₁ is

(1) --COOR₁, wherein R₁ is

(a) hydrogen;

(b) alkyl of one to 12 carbon atoms, inclusive;

(c) cycloalkyl of 3 to 10 carbon atoms, inclusive;

(d) aralkyl of 7 to 12 carbon atoms, inclusive;

(e) phenyl;

(f) phenyl substituted with one, two, or three chloro or alkyl of one to3 carbon atoms;

(g) phenyl substituted in the para position by

(i) --NH--CO--R₂₅

(ii) --CO--R₂₆

(iii) --O--CO--R₂₇

(iv) --CH═N--NH--CO--NH₂

wherein R₂₅ is methyl, phenyl, acetamidophenyl, benzamidophenyl, or--NH₂ ; R₂₆ is hydroxy, methyl, phenyl, --NH₂, or methoxy; and R₂₇ isphenyl or acetamidophenyl; inclusive, or a pharmacologically acceptablecation; or

(2) --COL₄, wherein L₄ is

(a) amino of the formula --NR₂₁ R₂₂, wherein R₂₁ and R₂₂ are

(i) hydrogen;

(ii) alkyl or one to 12 carbon atoms, inclusive;

(iii) cycloalkyl of 3 to 10 carbon atoms, inclusive;

(iv) aralkyl of 7 to 12 carbon atoms, inclusive;

(v) phenyl;

(vi) phenyl substituted with one, 2, or 3 chloro, alkyl of one to threecarbon atoms, inclusive, hydroxy, carboxy, alkoxycarbonyl of one to 4carbon atoms, inclusive, or nitro;

(vii) carboxyalkyl of 2 to 5 carbon atoms, inclusive;

(viii) carbamoylalkyl of 2 to 5 carbon atoms, inclusive;

(ix) cyanoalkyl of 2 to 5 carbon atoms, inclusive;

(x) acetylalkyl of 3 to 6 carbon atoms, inclusive;

(xi) benzoylalkyl of 7 to 11 carbon atoms, inclusive;

(xii) benzoylalkyl substituted by one, 2, or 3 chloro, alkyl of one to 3carbon atoms, inclusive, hydroxy, alkoxy of one to 3 carbon atoms,inclusive, carboxy, alkoxycarbonyl of one to 4 carbon atoms, inclusive,or nitro;

(xiii) pyridyl;

(xiv) pyridyl substituted by one, 2, or 3 chloro, alkyl of one to 3carbon atoms, inclusive, or alkoxy of one to 3 carbon atoms, inclusive;

(xv) pyridylalkyl of 6 to 9 carbon atoms, inclusive;

(xvi) pyridylalkyl substituted by one, 2, or 3 chloro, alkyl of one to 3carbon atoms, inclusive, hydroxy or alkoxy of one to 3 carbon atoms,inclusive;

(xvii) hydroxyalkyl of one to 4 carbon atoms, inclusive;

(xviii) dihydroxyalkyl of one to 4 carbon atoms, or

(xix) trihydroxyalkyl of one to 4 carbon atoms;

with the further proviso that not more than one of R₂₁ and R₂₂ is otherthan hydrogen or alkyl;

(b) cycloamino selected from the group consisting of

(i) pyrrolidino,

(ii) piperidino,

(iii) morpholino,

(iv) piperazino,

(v) hexamethyleneimino,

(vi) pyrrolino,

(vii) 3,4-didehydropiperidinyl, or (viii) pyrrolidino, piperidino,morpholino, piperazino, hexamethyleneimino, pyrrolino, or3,4-didehydropiperidinyl substituted by one or two alkyl of one to 12carbon atoms, inclusive;

(c) carbonylamino of the formula --NR₂₃ COR₂₁, wherein R₂₃ is hydrogenor alkyl of one to 4 carbon atoms and R₂₁ is other than hydrogen, butotherwise as defined above; or

(d) sulfonylamino of the formula --NR₂₃ SO₂ R₂₁, wherein R₂₁ and R₂₃ areas defined in (c);

With regard to the divalent substituents described above (e.g., L₁ andM₁), these divalent radicals are defined as α-R_(i) :β-R_(j), whereinR_(i) represents the substituent of the divalent moiety in the alphaconfiguration with respect to the plane of the ring and R_(j) representsthe substituent of the divalent moiety in the beta configuration withrespect to the plane of the ring. Accordingly, when M₁ is defined asα-OH:β-R₅, the hydroxy of the M₁ moiety is in the alpha configuration,i.e., as in PGF₂ above, and the R₅ substituent is in the betaconfiguration. Not all carbon atoms to which such divalent moieties areattached represent asymmetric centers. For example when both valencebonds are to hydrogen (e.g., L₁ is α-H:β-H), then no asymmetric centeris present.

The novel prostaglandin and prostacylcin analogs herein are all named as2,5-inter-o-phenylene-3,4-dinor-PG compounds. Formula VI compounds arefurther named as 5,9α-epoxy-9-deoxy- or5,9α-epoxy-9-deoxy-6,7-didehydro-PG compounds, depending on whether Z₂is --CH₂ CH₂ -- or cis-CH═CH--, respectively. Formula VI and formulaVIII compounds are further named as 6β-PGI₁ compounds in view of theirconfiguration at C-6.

The novel prostaglandin and prostacyclin analogs herein wherein R₈ ishydrogen or hydroxymethyl are respectively referred to as11-deoxy-PG-type or 11-deoxy-11-hydroxymethyl-PG-type compounds.Additionally, when R₁ is cis-CH═CH--, --CH₂ CH₂ --, or --C.tbd.C--, thenovel compounds thereby referred to are named as 13-cis-PG-type,13,14-dihydro-PG-type, or 13,14-didehydro-PG-type compounds,respectively.

Compounds herein wherein M₁ is α-OH:β-R₅ or α-R₅ :β-OH and R₅ is alkylare referred to as 15-alkyl-PG-type compounds.

With the exception of the 13-cis-PG-type compounds described above, allthe above compounds exhibiting a hydroxy or alkoxy moiety in the betaconfiguration at C-15 are additionally referred to as 15-epi-PG-typecompounds. For the 13-cis-PG-type compounds herein, only compoundsexhibiting the hydroxy or alkoxy moiety in the alpha configuration atC-15 are referred to as 15-epi-PG-type compounds. The rationale for thissystem of nomenclature with respect to the natural and epimericconfigurations at C-15 is described in U.S. Pat. No. 4,016,184, issuedApr. 5, 1977.

When R₇ is --(CH₂)_(m) --(CH₂)_(m) --CH₃, wherein m is as defined above,the novel compounds herein are named as 19,20-dinor-PG-type,20-nor-PG-type, 20-methyl-PG-type or 20-ethyl-PG-type compounds when mis one, 2, 4, or 5, respectively.

When R₇ is cis-CH═CH--CH₂ CH₃ --, the novel compounds herein are namedas PG₃ or cis-17,18-didehydro-PG compounds.

When R₇ is phenyl and neither R₃ nor R₄ is methyl, the compounds sodescribed are named as "16-phenyl-17,18,19,20-tetranor" compounds, whens is zero. When R₇ is substituted phenyl, the corresponding compoundsare named as "16-(substituted phenyl)17,18,19,20-tetranor" compounds.When one and only one of R₃ and R₄ is methyl or both R₃ and R₄ aremethyl, then the corresponding compounds wherein R₇ is as defined inthis paragraph are named as "16-phenyl or 16-(substitutedphenyl)-18,19,20-trinor" compounds or "16-methyl-16phenyl- or16-(substituted phenyl)-18,19,20-trinor" compounds, respectively.

When R₇ is phenylmethyl, the compounds so described are named as"17-phenyl-18,19,20-trinor" compounds. When R₇ is substitutedphenylmethyl the corresponding compounds are named as "17-(substitutedphenyl)-18,19,20-trinor" compounds.

When R₇ is phenylethyl the compounds so described as named as"18-phenyl-19,20-dinor" compounds, when s is 0. When s is one, 2, or 3,the corresponding compounds are named as "18-(substitutedphenyl)-19,20-dinor" compounds.

When R₇ is phenylpropyl, the compounds so described are named as"19-phenyl-20-nor" compounds. When R₇ is substituted phenylpropyl thecorresponding compounds are named as "19-(substituted phenyl)-20-nor"compounds.

When R₇ is phenoxy and neither R₃ nor R₄ is methyl, the compounds sodescribed are named as "16-phenoxy-17,18,19,20-tetranor" compounds. WhenR₇ is substituted phenoxy the corresponding compounds are named as"16-(substituted phenoxy)-17,18,19,20-tetranor" compounds. When one andonly one of R₃ and R₄ is methyl or both R₃ and R₄ are methyl, then thecorresponding compounds wherein R₇ is as defined in this paragraph arenamed as "16-phenoxy- or 16-(substituted phenoxy)-18,19,20-trinor"compounds or "16-methyl-16-phenoxy- or 16-(substitutedphenoxy)-18,19,20-trinor" compounds, respectively.

When at least one of R₃ and R₄ is not hydrogen then (except for the16-phenoxy or 16-phenyl compounds discussed above) there are describedthe "16-methyl" (one and only one of R₃ and R₄ is methyl),"16,16-dimethyl" (R₃ and R₄ are both methyl), "16-fluoro" (one and onlyone of R₃ and R₄ is fluoro), "16,16-difluoro" (R₃ and R₄ are bothfluoro) compounds. For those compounds wherein R₃ and R₄ are different,the prostaglandin analogs so represented contain an asymmetric carbonatom at C-16. Accordingly, two epimeric configurations are possible:"(16S)" and "(16R)". Further, there is described by this invention theC-16 epimeric mixture: "(16RS)".

Examples of novel amides herein (i.e., X₁ is --COL₄) include thefollowing:

(1) Amides within the scope of alkylamino groups of the formula --NR₂₁R₂₂ are methylamide, ethylamide, n-propylamide, n-butylamide,n-pentylamide, n-hexylamide, n-heptylamide, n-octylamide, n-nonylamide,n-decylamide, n-undecylamide, and n-dodecylamide, and isomeric formsthereof. Further examples are dimethylamide, diethylamide,di-n-propylamide, di-n-butylamide, methylethylamide, methylpropylamide,methylbutylamide, ethylpropylamide, ethylbutylamide, andpropylbutylamide. Amides within the scope of cycloalkylamino arecyclopropylamide, cyclobutylamide, cyclopentylamide,2,3-dimethylcyclopentylamide, 2,2-dimethylcyclopentylamide,2-methylcyclopentylamide, 3-tert-butylcyclopentylamide, cyclohexylamide,4-tert-butylcyclohexylamide, 3-isopropylcyclohexyl amide,2,2-dimethylcyclohexylamide, cycloheptylamide, cyclooctylamide,cyclononylamide, cyclodecylamide, N-methyl-N-cyclobutylamide,N-methyl-N-cyclopentylamide, N-methyl-N-cyclohexylamide,N-ethyl-N-cyclopentylamide, and N-ethyl-N-cyclohexylamide. Amides withinthe scope of aralkylamino are benzylamide, 2-phenylethylamide,2-phenylethylamide, and N-methyl-N-benzylamide. Amides within the scopeof substituted phenylamido are p-chloroanilide, m-chloroanilide,2,4-dichloroanilide, 2,4,6-trichloroanilide, m-nitroanilide,p-nitroanilide, p-methoxyanilide, 3,4dimethoxyanilide,3,4,5-trimethoxyanilide, p-hydroxymethylanilide, p-methylanilide,m-methylanilide, p-ethylanilide, t-butylanilide, p-carboxyanilide,p-methoxycarbonylanilide, o-carboxyanilide anilide and o-hydroxyanilide.Amides within the scope of carboxyalkylamino are carboxymethylamide,carboxyethylamide, carboxypropylamide, and carboxybutylamide. Amideswithin the scope of carbamoylalkylamino are carbamoylmethylamide,carbamoylethylamide, carbamoylpropylamide, and carbamoylbutylamide.Amides within the scope of cyanoalkylamino are cyanomethylamide,cyanoethylamide, cyanopropylamide, and cyanobutylamide. Amides withinthe scope of acetylalkylamino are acetylmethylamide, acetylethylamide,acetylpropylamide, and acetylbutylamide. Amides within the scope ofbenzoylalkylamino are benzoylmethylamide, benzoylethylamide,benzoylpropylamide, and benzoylbutylamide. Amides within the scope ofsubstituted benzoylalkylamino are p-chlorobenzoylmethylamide,m-chlorobenzoylmethylamide, 2,4-dichlorobenzoylmethylamide,2,4,6-trichlorobenzoylmethylamide, m-nitrobenzoylmethylamide,p-nitrobenzoylmethylamide, p-methoxybenzoylmethylamide,2,4-dimethoxybenzoylmethylamide, 3,4,5-trimethoxybenzoylmethylamide,p-hydroxymethylbenzoylmethylamide, p-methylbenzoylmethylamide,m-methylbenzoylmethylamide, p-ethylbenzoylmethylamide,t-butylbenzoylmethylamide, p-carboxybenzoylmethylamide,m-methoxycarbonylbenzoylmethylamide, o-carboxybenzoylmethylamide,o-hydroxybenzoylmethylamide, p-chlorobenzoylethylamide,m-chlorobenzoylethylamide, 2,4-dichlorobenzoylethylamide,2,4,6-trichlorobenzoylethylamide, m-nitrobenzoylethylamide,p-nitrobenzoylethylamide, p-methoxybenzoylethylamide,p-methoxybenzoylethylamide, 2,4-dimethoxybenzoylethylamide,3,4,5-trimethoxybenzoylethylamide, p-hydroxymethylbenzoylethylamide,p-methylbenzoylethylamide, m-methylbenzoylethylamide,p-ethylbenzoylethylamide, t-butylbenzoylethylamide,p-carboxybenzoylethylamide, m-methoxycarbonylbenzoylethylamide,o-carboxybenzoylethylamide, o-hydroxybenzoylethylamide,p-chlorobenzoylpropylamide, m-chlorobenzoylpropylamide,2,4-dichlorobenzoylpropylamide, 2,4,6-trichlorobenzoylpropylamide,m-nitrobenzoylpropylamide, p-nitrobenzoylpropylamide,p-methoxybenzoylpropylamide, 2,4-dimethoxybenzoylpropylamide,3,4,5-trimethoxybenzoylpropylamide, p-hydroxymethylbenzoylpropylamide,p-methylbenzoylpropylamide, m-methylbenzoylpropylamide,p-ethylbenzoylpropylamide, t-butylbenzoylpropylamide,p-carboxybenzoylamide, m-methoxycarbonylbenzoylpropylamide,o-carboxybenzoylpropylamide, o-hydroxybenzoylpropylamide,p-chlorobenzoylbutylamide, m-chlorobenzoylbutylamide,2,4-dichlorobenzoylbutylamide, 2,4,6-trichlorobenzoylbutylamide,m-nitrobenzoylmethylamide, p-nitrobenzoylbutylamide,p-methoxybenzoylbutylamide, 2,4-dimethoxybenzoylbutylamide,3,4,5-trimethoxybenzoylbutylamide, p-hydroxymethylbenzoylbutylamide,p-methylbenzoylbutylamide, m-methylbenzoylbutylamide,p-ethylbenzoylbutylamide, m-methylbenzoylbutylamide,p-ethylbenzoylbutylamide, t-butylbenzoylbutylamide,p-carboxybenzoylbutylamide, m-methoxycarbonaylbenzoylbutylamide,o-carboxybenzoylbutylamide, o-hydroxybenzoylmethylamide. Amides withinthe scope of pyridylamino are α-pyridylamide, β-pyridylamide, andγ-pyridylamide. Amides within the scope of substituted pyridylamino are4-methyl-α-pyridylamide, 4-methyl-β-pyridylamide,4-chloro-α-pyridylamide, and 4-chloro-β-pyridylamide. Amides within thescope of pyridylalkylamino are α-pyridylmethylamide,β-pyridylmethylamide, γ-pyridylmethylamide, α-pyridylethylamide,β-pyridylethylamide, γ-pyridylethylamide, α-pyridylpropylamide,β-pyridylpropylamide, γ-pyridylpropylamide, α-pyridylbutylamide,β-pyridylbutylamide, and γ-pyridylbutylamide. Amides within the scope ofsubstituted pyridylalkylamido are 4-methyl-α-pyridylmethylamide,4-methyl-β-pyridylmethylamide, 4-chloro-α-pyridylmethylamide,4-chloro-β-pyridylmethylamide, 4-methyl-α-pyridylpropylamide,4-methyl-β-pyridylpropylamide, 4-chloro-α-pyridylpropylamide,4-chloro-β-pyridylpropylamide, 4-methyl-α-pyridylbutylamide,4-methyl-β-pyridylbutylamide, 4-chloro-α-pyridylbutylamide,4-chloro-β-pyridylbutylamide, 4-methyl-β-pyridylbutylamide. Amideswithin the scope of hydroxyalkylamino are hydroxymethylamide,α-hydroxyethylamide, β-hydroxyethylamide, α-hydroxypropylamide,β-hydroxypropylamide, γ-hydroxypropylamide, 1-(hydroxymethyl)ethylamide,1-(hydroxymethyl)propylamide, (2-hydroxymethyl)propylamide, andα,α-dimethyl-β-hydroxyethylamide. Amides within the scope ofdihydroxyalkylamino are dihydroxymethylamide, α,α-dihydroxyethylamide,α,β-dihydroxyethylamide, β,β-dihydroxyethylamide,α,α-dihydroxypropylamide, α,β-dihydroxypropylamide,α,γ-dihydroxypropylamide, β,β-dihydroxypropylamide,β,γ-dihydroxypropylamide, γ,γ-dihydroxypropylamide,1-(hydroxymethyl)-2-hydroxymethylamide,1-(hydroxymethyl)-1-hydroxyethylamide, α,α-dihydroxybutylamide,α,β-dihydroxybutylamide, α,γ-dihydroxybutylamide,α,δ-dihydroxybutylamide, β,β-dihydroxybutylamide,β,γ-dihydroxybutylamide, β,δ-dihydroxybutylamide,γ,γ-dihydroxybutylamide, γ, δ-didihydroxybutylamide,δ,δ-dihydroxybutylamide, and 1,1-bis(hydroxymethyl)ethylamide. Amideswithin the scope of trihydroxyalkylamino aretris(hydroxymethyl)methylamide and1,3-dihydroxy-2-hydroxymethylpropylamide.

(2) Amides within the scope of cycloamino groups described above arepyrrolidylamide, piperidylamide, morpholinylamide,hexamethyleneiminylamide, piperazinylamide, pyrrolinylamide, and3,4-didehydropiperidinylamide.

(3) Amides within the scope of carbonylamino of the formula --NR₂₃ COR₂₁are methylcarbonylamide, ethylcarbonylamide, phenylcarbonylamide, andbenzylcarbonylamide.

(4) Amides within the scope of sulfonylamino of the formula --NR₂₃ SO₂R₂₁ are methylsulfonylamide, ethylsulfonylamide, phenylsulfonylamide,p-tolylsulfonylamide, benzylsulfonylamide.

Examples of alkyl of one to 12 carbon atoms, inclusive, are methyl,ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl,undecyl, dodecyl, and isomeric forms thereof.

Examples of cycloalkyl of 3 to 10 carbon atoms, inclusive, whichincludes alkyl-substituted cycloalkyl, are cyclopropyl,2-methylcyclopropyl, 2,2-dimethylcyclopropyl, 2,3-diethylcyclopropyl,2-butylcyclopropyl, cyclobutyl, 2-methylcyclobutyl, 3-propylcyclobutyl,2,3,4-triethylcyclobutyl, cyclopentyl, 2,2-dimethylcyclopentyl,2-pentylcyclopentyl, 3-tert-butylcyclopentyl, cyclohexyl,4-tert-butylcyclohexyl, 3-isopropylcyclohexyl, 2,2-dimethylcyclohexyl,cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl.

Examples of aralkyl of 7 to 12 carbon atoms, inclusive, are benzoyl,2-phenethyl, 1-phenylethyl, 2-phenylpropyl, 4-phenylbutyl,3-phenylbutyl, 2-(1-napthylethyl), and 1-(2-napthylmethyl).

Examples of phenyl substituted by one to 3 chloro or alkyl or one to 4carbon atoms, inclusive, are p-chlorophenyl, m-chlorophenyl,2,4-dichlorophenyl, 2,4,6-trichlorophenyl, p-tolyl, m-tolyl, o-tolyl,p-ethylphenyl, p-tertbutylphenyl, 2,5-dimethylphenyl,4-chloro-2-methylphenyl, and 2,4-dichloro-3-methylphenyl.

Examples of substituted phenoxy, phenylmethyl, phenylethyl, orphenylpropyl of the R₇ moiety are (o-, m-, or p-)tolyl, (o-, m-, orp-)ethylphenyl, 2-ethyltolyl, 4-ethyl-o-tolyl, 5-ethyl-m-tolyl, (o-, m-,or p-)propylphenyl, 2-propyl-(o-, m-, or p-)tolyl,4-isopropyl-2,6-xylyl, 3-propyl-4-ethylphenyl, (2,3,4-, 2,3,5-, 2,3,6-,or 2,4,5-)trimethylphenyl, (o-, m-, or p-)fluorophenyl, 2-fluoro-(o-,m-, or p-)tolyl, 4-fluoro-2,5-xylyl, (2,4-, 2,5-, 2,6-, 3,4-, or3,5-)difluorophenyl, (o-, m-, or p-)chlorophenyl, 2-chloro-p-tolyl,(3-,4-,5-, or 6-)chloro-o-tolyl, 4-chloro-2-propylphenyl,2-isopropyl-4-chlorophenyl, 4-chloro-3,5-xylyl, (2,3-2,4-, 2,5-, 2,6-,3,4-, or 3,5-)dichlorophenyl, 4-chloro-3-fluorophenyl, (3- or4-)chloro-2-fluorophenyl, (o-, m-, or p-)trifluoromethylphenyl, (o-, m-,or p-)methoxyphenyl, (o-, m-, or p-)ethoxyphenyl, (4- or5-)chloro-2-methoxyphenyl, 2,4-dichloro-(4- or 6-)methylphenyl, (o-, m-,or p-)tolyloxy, (o-, m-, or p-)ethylphenyloxy, 2-ethyltolyloxy,4-ethyl-o-tolyloxy, 5-ethyl-m-tolyloxy, (o-, m-, or p-) propylphenoxy,2-propyl-(o-, m-, or p-)tolyloxy, 4-isopropyl-2,6-xylyloxy,3-propyl-4-ethylphenyloxy, (2,3,4-, 2,3,5-, 2,3,6-, or2,4,5-)trimethylphenoxy, (o-, m-, or p-)fluorophenoxy, 2-fluoro-(o-, m-,or p-)tolyloxy, 4-fluoro-2,5-xylyloxy, (2,4-, 2,5-, 2,6-, 3,4-, or3,5-)difluorophenoxy, (o-, m-, or p-)-chlorophenoxy,2-chloro-p-tolyloxy, (3-, 4-, 5, or 6-)chloro-o-tolyloxy,4-chloro-2-propylphenoxy, 2-isopropyl-4-chlorophenoxy,4-chloro-3,5-xylyloxy, (2,3-, 2,4-, 2,5-, 2,6-, 3,4-, or3,5-)dichlorophenyloxy, 4-chloro-3-fluorophenoxy, (3- or4-)chloro-2-fluorophenoxy, (o-, m-, or p-)trifluoromethylphenoxy, (o-,m-, or p-)methoxyphenoxy, (o-, m-, or p-)ethoxyphenoxy, (4- or5-)chloro-2-methoxyphenoxy, 2,4-dichloro-(5- or 6-)methylphenoxy, (o-,m-, or p-)tolylmethyl, (o-, m-, or p-)ethylphenylmethyl,2-ethyltolylmethyl, 4-ethyl-o-tolylmethyl, 5-ethyl-m-tolylmethyl, (o-,m-, or p-)propylphenylmethyl, 2-propyl-(o-, m-, or p-)tolylmethyl,4-isopropyl-2,6-xylylmethyl, 3-propyl-4-ethylphenylmethyl, (2,3,4-,2,3,5-, 2,3,6-, or 2,4,5-)trimethylphenylmethyl, (o-, m-, orp-)fluorophenylmethyl, 2-fluoro-(o-, m-, or p-)tolylmethyl,4-fluoro-2,5-xylylmethyl, (2,4-, 2,5-, 2,6-, 3,4-, or3,5-)difluorophenyl, (o-, m-, or p-)chlorophenylmethyl,2-chloro-p-tolylmethyl, (3-, 4-, 5-, or 6-)chloro-o-tolyl-methyl,4-chloro-2-propylphenylmethyl, 2-isopropyl-4-chlorophenylmethyl,4-chloro-3,5-xylylmethyl, (2,3-, 2,4-, 2,5-, 2,6-, 3,4-, or3,5-)dichlorophenylmethyl, 4-chloro-3-fluorophenylmethyl, (3- or4-)chloro-2-fluorophenylmethyl, (o-, m-, orp-)trifluoromethylphenylmethyl, (o-, m-, or p-)methoxyphenylmethyl, (o-,m-, or p-)ethoxyphenylmethyl, (4- or 5-)chloro-2-methoxyphenylmethyl,and 2,4-dichloro-(4- or 6-)methoxyphenylmethyl.

The term "pharmacologically acceptable cation" refers to thosepharmacologically acceptable salts of the prostaglandin- orprostacyclin-type carboxylic acids (X₁ is --COOH) described above whichare conventionally employed with prostaglandins. In particular, suchpharmacologically acceptable salts include pharmacologically acceptablemetal cations, amine cations, and quarternary ammonium cations.Additionally basic amino acids such as arginine and lysine are employed.Further, certain amine cations such as THAM[tris(hydroxymethyl)aminomethyl] and adamantanamine as especially usefulfor the present purposes. Additionally, U.S. Pat. No. 4,016,184, issuedApr. 5, 1977 (particularly column 29), describes salts which arelikewise preferred for the present purposes.

The novel prostaglandin and prostacyclin analogs disclosed hereinproduce certain prostacyclin-like pharmacological responses.

Accordingly, the novel prostaglandin and prostacyclin analogs disclosedherein are used as agents in the study, prevention, control, andtreatment of diseases, and other undesirable physiological conditions,in mammals, particularly humans, valuable domestic animals, pets,zoological specimens, and laboratory animals (e.g., mice, rats, rabbitsand monkeys). In particular, these compounds have useful application assmooth muscle stimulators, antihypertensive agents, antithromboticagents, antiulcer agents, antiasthma agents, and antidermatosis agents,as indicated below.

(a) Smooth Muscle Stimulation

The novel prostaglandin and prostacylcin analogs herein are extremelypotent in causing stimulation of smooth muscle, and are also highlyactive in potentiating other known smooth muscle stimulators, forexample, oxytocic agents, e.g., oxytocin, and the various ergotalkaloids including derivatives and analogs thereof. Therefore, they areuseful in place of or in combination with less than usual amounts ofthese known smooth muscle stimulators, for example, to relieve thesymptoms of paralytic ileus, or to control or prevent atonic uterinebleeding after abortion or delivery, to aid in expulsion of theplacenta, and during the puerperium. For the latter purpose the compoundis administered by intravenous infusion immediately after abortion ordelivery at a dose in the range about 0.01 to about 50 μg per kg of bodyweight per minute until the desired effect is obtained. Subsequent dosesare given by intravenous, subcutaneous, or intramuscular injection orinfusion during puerperium in the range 0.01 to 2 mg per kg of bodyweight per day, the exact dose depending on the age, weight andcondition of the patient or animal.

(b) Platelet Aggregation Inhibition

These novel prostaglandin and prostacyclin analogs are useful wheneverit is desired to inhibit platelet aggregation, to reduce the adhesivecharacter of platelets, or to remove or prevent the formation of thrombiin mammals, including man. For example, these compounds are useful inthe treatment and prevention of myocardial infarcts, to treat andprevent post-operative thrombosis, to promote patency of vascular graftsfollowing surgery, and to treat conditions such as atherosclerosis,arteriosclerosis, blood clotting defects due to lipemia, and otherclinical conditions in which the underlying etiology is associated withlipid imbalance or hyperlipidemia. Other in vivo applications includegeriatric patients to prevent cerebral ischemic attacks and long termprophylaxis following myocardial infarcts and strokes. For thesepurposes, these compounds are administered systemically, e.g.,intravenously, subcutaneously, intramuscularly, and in the form ofsterile implants for prolonged action. For rapid response, especially inemergency situations, the intravenous route of administration ispreferred. Doses in the range about 0.01 to about 10 mg per kg of bodyweight per day are used, the exact dose depending on the age, weight,and condition of the patient or animal, and on the frequency and routeof administration.

The preferred dosage form for these compounds is oral, although othernon-parenteral routes (e.g., buccal, rectal, sublingual) are likewiseemployed in preference to parenteral routes. Oral dosage forms areconventionally formulated (tablets, capsules, et cetera) andadministered 2 to 4 times daily. Doses in the range of about 0.05 to 100mg/kg of body weight per day are effective.

The addition of these compounds to whole blood provides in vitroapplications such as storage of whole blood to be used in heart-lungmachines. Additionally whole blood containing these compounds can becirculated through organs, e.g., heart and kidneys, which have beenremoved from a donor prior to transplant. They are also useful inpreparing platelet rich concentrates for use in treatingthrombocytopenia, chemotherapy, and radiation therapy. In vitroapplications utilize a dose of 0.001-1.0 μg per ml of whole blood.

(c) Blood Pressure Reduction

The novel prostaglandin and prostacyclin analogs herein are useful ashypotensive agents to reduce blood pressure in mammals, including man.For this purpose, the compounds are administered by intravenous infusionat the rate about 0.01 to about 50 μg per kg of body weight per minuteor in single or multiple doses of about 25 to 500 μg per kg of bodyweight total per day.

As for the antithrombotic application described above, these compoundsare most preferably administered orally or by other convenientnon-parenteral dosage form. In determining the appropriate oral dosageand frequency of administration, titration of dose in conjunction withother antihypertensive drugs being concomitantly administered isrequired. When used as the sole antihypertensive agent, determining theminimum effective dose required for adequate control of blood pressureis undertaken by initiating therapy at or near the threshold dose ofpatient or animal response. Thereafter upward adjustment of the dosage,until full control is achieved or undesired side effects are observed,is undertaken. Accordingly threshold dosages of 0.01 to 1.0 mg per kg ofbody weight are employed.

(d) Gastric Secretion Reduction

These novel prostaglandin and prostacyclin analogs are also useful inmammals, including man and certain useful animals, e.g., dogs and pigs,to reduce and control gastric secretion, thereby to reduce or avoidgastrointestinal ulcer formation, and accelerate the healing of suchulcers already present in the gastrointestinal tract. For this purpose,these compounds are injected or infused intravenously, subcutaneously,or intramuscularly in an infusion dose range about 0.1 μg to about 20 μgper kg of body weight per minute, or in a total daily dose by injectionor infusion in the range about 0.01 to about 10 mg per kg of body weightper day, the exact dose depending on the age, weight, and condition ofthe patient or animal, and on the frequency and route of administration.

Preferably, however, these novel compounds are administered orally or byother non-parenteral routes. As employed orally, one to 6administrations daily in a dosage range of about 1.0 to 100 mg per kg ofbody weight per day is employed. Once healing of the ulcers has beenaccomplished the maintenance dosage required to prevent recurrence isadjusted downward so long as the patient or animal remains asymptomatic.

(e) NOSAC-Induced Lesion Inhibition

These novel prostaglandin and prostacyclin analogs herein are alsouseful in reducing the undesirable gastrointestinal effects resultingfrom systemic administration of anti-inflammatory prostaglandinsynthetase inhibitors, and are useful for that purpose by concomitantadministration of the prostaglandin derivative and the anti-inflammatoryprostaglandin synthetase inhibitor. See Partridge, et al., U.S. Pat. No.3,781,429, for a disclosure that the ulcerogenic effect induced bycertain non-steroidal anti-inflammatory agents in rats is inhibited byconcomitant oral administration of certain prostaglandins. Accordinglythese novel prostaglandin and prostacyclin analogs herein are useful,for example, in reducing the undesirable gastrointestinal effectsresulting from systemic administration of indomethacin, phenylbutazone,and aspirin. These are substances specifically mentioned in Partridge,et al. as non-steroidal, anti-inflammatory agents. These are also knownto be prostaglandin synthetase inhibitors.

The anti-inflammatory synthetase inhibitor, for example, indomethacin,aspirin, or phenylbutazone is administered in any of the ways known inthe art to alleviate an inflammatory condition, for example, in anydosage regimen and by any of the known routes of systemicadministration.

(f) Bronchodilation (Antiasthma)

These novel prostaglandin and prostacyclin analogs are also useful inthe treatment of asthma. For example, these compounds are useful asbronchodilators or as inhibitors of mediator-inducedbronchoconstriction, such as SRS-A, and histamine which are releasedfrom cells activated by an antigen-antibody complex. Thus, thesecompounds control spasm and facilitate breathing in conditions such asbronchial bronchitis, bronchiectasis, pneumonia and emphysema. For thesepurposes, these compounds are administered in a variety of dosage forms,e.g., orally in the form of tablets, capsules, or liquids; rectally inthe form of suppositories, parenterally, subcutaneously, orintramuscularly, with intravenous administration being preferred inemergency situations; by inhalation in the form of aerosols or solutionsfor nebulizers; or by insufflation in the form of powder. Doses in therange of about 0.01 to 5 mg per kg of body weight are used 1 to 4 timesa day, the exact dose depending on the age, weight, and condition of thepatient and on the frequency and route of administration. For the aboveuse these prostaglandin and prostacyclin analogs can be combinedadvantageously with other anti-asthmatic agents, such assympathomimetics (isoproterenol, phenylephrine, ephedrine, etc.);xanthine derivatives (theophylline and aminophylline); andcorticosteroids (ACTH and prednisolone).

These compounds are effectively administered to human asthma patients byoral inhalation or by aerosol inhalation. For administration by the oralinhalation route with conventional nebulizers or by oxygenaerosolization it is convenient to provide the instant active ingredientin dilute solution, preferably at concentrations of about one part ofmedicament to form about 100 to 200 parts by weight of total solution.Entirely conventional additives may be employed to stabilize thesesolutions or to provide isotonic media, for example, sodium chloride,sodium citrate, citric acid, sodium bisulfite, and the like can beemployed. For administration as a self-propelled dosage unit foradministering the active ingredient in aerosol form suitable forinhalation therapy the composition can comprise the active ingredientsuspended in an inert propellant (such as a mixture ofdichlorodifluoromethane and dichlorotetrafluoroethane) together with aco-solvent, such as ethanol, flavoring materials and stabilizers.Instead of a co-solvent there can also be used a dispensing agent suchas ethyl alcohol. Suitable means to employ the aerosol inhalationtherapy technique are described fully in U.S. Pat. No. 3,868,691, forexample.

(g) Dermatosis Reversal

These novel prostaglandin and prostacyclin analogs are useful fortreating proliferating skin diseases of man and domesticated animals,including psoriasis, atopic dermatitis, non-specific dermatitis, primaryirritant contact dermatitis, allergic contact dermatitis, basal andsquamous cell carcinomas of the skin, lamellar ichthyosis, epidermolytichyperkeratosis, premalignant sun-induced keratosis, non-malignantkeratosis, acne, and seborrheic dermatitis in humans and atopicdermatitis and mange in domesticated animals. These compounds alleviatethe symptoms of these proliferative skin diseases: psoriasis, forexample, being alleviated when a scale-free psoriasis lesion isnoticeably decreased in thickness and noticeably, but incompletelycleared, or completely cleared.

For these purposes, these compounds are applied topically ascompositions including a suitable pharmaceutical carrier, for example asan ointment, lotion, paste, jelly, spray, or aerosol, using topicalbases such as petrolatum, lanolin, polyethylene glycols, and alcohols.These compounds, as the active ingredients, constitute from about 0.1%to about 15% by weight of the composition, preferably from about 0.5% toabout 2%. In addition to topical administration, injection may beemployed, as intradermally, intra- or peri-lesionally, orsubcutaneously, using appropriate sterile saline compositions.

Within the scope of the novel prostaglandin and prostacyclin analogsdescribed above, certain compounds are preferred in that they exhibitincreased potency, selectivity of action, or otherwise representespecially convenient and useful agents. Preferred are the formula Vcompounds, especially those wherein Z₂ is cis-CH═CH--.

With respect to the Y₁ moiety, preferred compounds are those wherein Y₁is trans-CH═CH-- or --CH₂ CH₂ --, the most especially preferredcompounds being those wherein Y₁ is trans-CH═CH--. With respect to theM₁ moiety, preferred compounds are those wherein M₁ is α-OH:β-R₅.

With respect to the L₁ moiety, those compounds wherein R₃ and R₄ are thesame are preferred. Further preferred are those compounds herein whereinat least one of R₃, R₄, and R₅ is hydrogen. In the event Y₁ iscis-CH═CH-- or --C.tbd.C--, compounds wherein R₃, R₄, and R₅ are allhydrogen are preferred.

With respect to the integer m, it is preferred that m be 3. Among thecompounds wherein R₇ is aromatic, the preferred compounds are the phenylor phenylmethyl compounds either unsubstituted or substituted by one ofchloro, fluoro, or trifluoromethyl.

With respect to the novel amides herein, preferred compounds are thosewherein R₂₁ and R₂₂ are preferably hydrogen or alkyl of one to 8 carbonatoms, inclusive, being the same or different, preferably with the totalnumber of carbon atoms in R₂₁ and R₂₂ being less than or equal to 8.More especially preferred are those amides wherein R₂₁ and R₂₂ arehydrogen or alkyl of one to 4 carbon atoms, inclusive, being the same ordifferent, with the total number of carbon atoms in R₂₁ and R₂₂ beingless than or equal to 4. Further R₂₃ is preferably hydrogen.

Of the various esters, methyl is most preferred with alkyl of one to 4carbon atoms, para-substituted phenyl and alkylcarbonylphenyl being alsopreferred.

The chart herein describes the method by which the novel prostaglandinor prostacyclin analogs herein are prepared from known or readilysynthesized starting materials.

With respect to this chart, L₁, M₁, M₈, X₁, Y₁, R₇, R₈, and R₂₈ are asdefined above.

R₂₈ is --OR₁₀, --CH₂ OR₁₀, or hydrogen, wherein R₁₀ is a blocking groupas defined above. In particular R₁₀ is a readily acid hydrolyzableblocking group such as tetrahydrofuranyl or tetrahydropyranyl. Forexamples of blocking groups especially contemplated by the presentinvention see U.S. Pat. No. 4,016,184, issued Apr. 5, 1977. R₁₉ is--Si(G₁)3, silyl groups, particularly those described in U.S. Pat. No.4,016,184. For the purposes of the present invention stable silyl groupssuch as t-butyldimethylsilyl are especially contemplated.

M₈ is α-R₅ :β-OR₁₀ or α-OR₁₀ :β-R₅, wherein R₅ and R₁₀ are as definedabove.

Y₂ is trans-CH═CH--, cis-CH═CH--, --CH₂ CH₂ --, or trans-CH═C(Hal),wherein Hal is chloro, bromo, or iodo.

With respect to Chart A a method is provided whereby the novel compoundsof formula XXII-XXVIII are prepared.

The various formula XXI compounds employed as starting materials in thepresent synthesis are conveniently prepared from known or readilyavailable starting materials. Formula XXI encompasses compoundsdeoxygenated at the latent C-11 (for preparing 11-deoxy-PGI₁ -typecompounds) or substituted at the latent C-11 by an hydroxymethyl inplace of the hydroxy (for preparing 11-deoxy-11-hydroxymethyl-PGI₁ -typecompounds). These compounds are prepared by methods known in the artfrom the corresponding 11-deoxy- or 11-deoxy-11-hydroxymethyl-PG's.

The formula XXII compound is prepared from the formula XXI compound by aWittig reaction, employing a triphenylphosphonium reagent of the formulaBr--(Ph)₃ P⁺ CH₂ --(o-Ph)--CH₂ --COOH, wherein Ph is phenyl and o-Ph isortho-phenylene. When Y₂ is trans-CH═C(Hal)-- the Wittig reaction isfollowed by dehydrohalogenation as described in U.S. Pat. No. 4,029,681.

The formula XXIII pharmacologically acceptable salts of the formula XXIIcarboxylic acids are then obtained by neutralization with acorresponding base. Conventional techniques of isolation and recovery ofthe salt are employed.

With respect to the novel formula XXIII PG-type amides (X₁ is --COL₄)and esters, especially p-substituted phenyl esters (R₁ is p-substitutedphenyl), such compounds from the formula XXII acids are prepared asfollows:

With regard to the preparation of the esters, especially p-substitutedphenyl esters disclosed herein, such compounds are prepared by themethod described in U.S. Pat. No. 3,890,372. Accordingly, by thepreferred method described therein, the p-substituted phenyl ester isprepared first by forming a mixed anhydride, particularly following theprocedures described below for preparing such anhydrides as the firststep in the preparation of amino and cycloamino derivatives.

This PG-type anhydride is then reacted with a solution of the phenolcorresponding to the p-substituted phenyl ester to be prepared. Thisreaction proceeds preferably in the presence of a tertiary amine such aspyridine. When the conversion is complete, the p-substituted phenylester has been recovered by conventional techniques.

Having prepared the PG-type carboxylic acids, the correspondingcarboxyamides are then prepared by one of several amidation methodsknown in the prior art. See, for example, U.S. Pat. No. 3,981,868,issued Sept. 21, 1976, for a description of the preparation of thepresent amino and cycloamino derivatives of prostaglandin-type freeacids and U.S. Pat. No. 3,954,741, describing the preparation ofcarbonylamino and sulfonylamino derivatives of prostaglandin-type freeacids.

The preferred method by which the present amino and cycloaminoderivatives of the novel prostacyclin-type free acids are prepared is,first by transformation of such free acids to corresponding mixed acidanhydrides. By this procedure, the prostaglandin-type free acid is firstneutralized with an equivalent of an amine base, and thereafter reactedwith a slight stoichiometric excess of a chloroformate corresponding tothe mixed anhydride to be prepared.

The amine base preferred for neutralization is triethylamine, althoughother amines (e.g., pyridine, methyldiethylamine) are likewise employed.Further, a convenient, readily available chloroformate for use in themixed anhydride production is isobutyl chloroformate.

The mixed anhydride formation proceeds by conventional methods andaccordingly the PGF-type free acid is mixed with both the tertiary aminebase and the chloroformate in a suitable solvent (e.g., aqueoustetrahydrofuran), allowing the reaction to proceed at -10° to 20° C.

Thereafter, the mixed anhydride is converted to the corresponding aminoor cycloamino derivative by reaction with the amine corresponding to theamide to be prepared. In the case where the simple amide (--NH₂) is tobe prepared, the transformation proceeds by the addition of ammonia.Accordingly, the corresponding amine (or ammonia) is mixed with themixed anhydride at or about -10° to +10° C., until the reaction is shownto be complete. For highly volatile amines, acid addition salts thereof(e.g., methylamine hydrochloride) are employed in place of thecorresponding free base (e.g., methylamide).

Thereafter, the novel PGF-type amino or cycloamino derivative isrecovered from the reaction mixture by conventional techniques.

The carbonylamino and sulfonylamino derivatives of the presentlydisclosed PG-type compounds are likewise prepared by known methods. See,for example, U.S. Pat. No. 3,954,741 for a description of the methods bywhich such derivatives are prepared. By this known method, theprostaglandin-type free acid is reacted with a carboxyacyl and sulfonylisocyanate, corresponding to the carbonylamino or sulfonylaminoderivative to be prepared.

By another, more preferred method the sulfonylamino derivatives of thepresent compounds are prepared by first generating the PG-type mixedanhydride, employing the method described above for the preparation ofthe amino and cycloamino derivatives. Thereafter, the sodium salt of thecorresponding sulfonamide is reacted with the mixed anhydride andhexamethylphosphoramide. The pure PG-type sulfonylamido derivative isthen obtained from the resulting reaction mixture by conventionaltechniques.

The sodium salt of the sulfonamide corresponding to the sulfonylaminoderivatives to be prepared is generated by reacting the sulfonamide withalcoholic sodium methoxide. Thus, by a preferred method, methanolicsodium methoxide is reacted with an equal molar amount of thesulfonamide. The sulfonamide is then reacted, as described above, withthe mixed anhydride, using about four equivalents of the sodium salt perequivalent of anhydride. Reaction temperatures at or about 0° C. areemployed.

With regard to the phenacyl or substituted phenacyl esters herein, seeU.S. Pat. No. 3,979,440 for a description of their preparations.

The formula XXIV and XXV compounds are prepared as a mixture from theformula XXIII compound by iodination and cyclization. Examples of suchcyclization procedures are provided in Staninets and Schilof, ChemicalAbstracts 64:21625H (1966). Iodination proceeds in an aqueous systemcontaining iodide, potassium iodide, and an alkali carbonate orbicarbonate. Optionally iodination proceeds in organic solvent systemssuch as dichloromethane containing iodine in the presence of an alkalimetal carbonate. While reaction temperatures below about 25° C. areemployed, most preferably reaction temperatures about 0°-5° C. yield thedesired product. When thin layer chromatographic analysis indicates thereaction is complete (e.g., 10-20 hr), the reaction mixture is quenchedwith addition of sodium sulfite and sodium carbonate, thereby yieldingthe desired product. Optionally to the method of Chart A, brominationrather than iodination may be employed. Accordingly there is prepared abromo compound corresponding to the formula XXIV iodo compound, which isused in subsequent reaction steps of Chart A. In undertaking such abromination, agents such as N-bromosuccinimide or N-bromoacetamide areemployed. See Fieser, et al., Reagents for Organic Synthesis, Vol. I,pages 74 and 78, and Vol. IV, page 51, John Wiley and Sons, New York,N.Y.

Thereafter the formula XXVI and XXVIII products are prepared from themixture of formula XXIV and XXV compounds by reductive deiodination.Useful reagents for this purpose include tributyltin hydride,triphenyltinhydride, sodium borohydride and dimethylsulfoxide, and zincin acetic acid. The especially preferred deiodination reagent istributyltin freshly prepared from tributyltin chloride and a lithiumaluminum hydride. The reaction proceeds in an organic solvent,preferably benzene, at 15°-35° C. Reaction mixtures are maintained untilsilica gel TLC analysis indicates the reaction is complete. Conventionalseparation techniques (e.g., column chromotography) yield pure formulaXXVI or XXVIII products.

Also prepared from the formula XXV compound is the formula XXVIIcompound by dehydrohalogenation or dehydroiodination. Dehydroiodinationreagents for this purpose are known in the art, for example, see Fieser,Reagents for Organic Synthesis, page 1308, John Wiley and Sons, NewYork, N.Y. (1966). Preferred dehydroiodinating reagents are tertiaryamines, sodium or potassium superoxides, sodium or potassium carbonates,sodium or potassium hydroxides, sodium or potassium benzoates, sodium orpotassium acetates, sodium or potassium trifluoroacetates, sodium orpotassium bicarbonates, silver acetate or a tetraalkylammoniumsuperoxide. Of the tertiary amines, 1,5-diazabicyclo[4.3.0]nonene-5(DBN) and 1,5-diazabicyclo[5.4.0]undecene-5 (DBU) are preferred.

For a description of the superoxides employed in this transformation seeJohnson, R. A., et al., Org. Chem. 40:1680 (1975). Also, the large scalegeneration of superoxides is described in Dietz, et al., J. Chem. Soc.(B), 1970, pages 816-820.

Dehydroiodination is carried out in an organic medium, such as toluene,and is monitored by silica gel TLC to determine the completion of thereaction. Ordinarily reaction temperatures at about ambient temperatureare employed, although somewhat higher temperatures (e.g., 40°-80° C.)are also useful in accelerating the reaction.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The invention can be more fully understood by the following examples andpreparations.

All temperatures are in degrees centigrade.

DBN is 1,5-diazabicyclo[4.3.0]nonene-5.

DBU is 1,5-diazabicyclo[5.4.0]undecene-5.

IR (infrared) absorption spectra are recorded on a Perkin-Elmer Model421 infrared spectrophotometer. Except when specified otherwise,undiluted (neat) samples are used.

UV (Ultraviolet) spectra are recorded on a Cary Model 15spectrophotometer.

NMR (Nuclear Magnetic Resonance) spectra are recorded on a Varian A-60,A-60D, or T-60 spectrophotometer in deuterochloroform solutions withtetramethylsilane as an internal standard (downfield).

Mass spectra are recorded on an CEG model 110B double Focusing HighResolution Mass Spectrometer or an LKB Model 9000 Gas-Chromatograph-MassSpectrometer. Trimethylsilyl derivatives are used, except whereotherwise indicated.

"Brine", herein, refers to an aqueous saturated sodium chloridesolution.

The A-IX solvent system used in thin layer chromatography is made upfrom ethyl acetate-acetic acid-2,2,4-trimethylpentane-water(90:20:50:100) according to M. Hamberg and B. Samuelsson, J. Biol. Chem.241, 258 (1966).

Skellysolve-B (SSB) refers to mixed isomeric hexanes.

Silica gel chromatography, as used herein, is understood to includeelution, collection of fractions and combination of those fractionsshown by TLC (thin layer chromatography) to contain the pure product(i.e., free of starting material and impurities).

Melting points (MP) are determined on a Fisher-John or Thomas-Hoovermelting point apparatus.

THF refers to tetrahydrofuran.

Specific Rotations, (α), are determined for solutions of a compound inthe specified solvent at ambient temperature with a Perkin-Elmer Model141 Automatic Polarimeter.

Example 1

A. o-[(carboxymethyl)benzyl]triphenylphosphonium bromide.

3-Isochromanone (30 g), Mann, F. G. and Stewart, F. H., Journal of theChemical Society 2819 (1954) is added with swirling to 150 ml ofhydrobromic acid (48%) at 80° C. The resulting mixture is then heated ona steam bath with occasional swirling for 10 min and thereafter pouredinto a mixture of crushed ice and water (750 g). The resulting mixtureis then extracted with ethyl acetate and the ethyl acetate extractswashed with a mixture of water and brine (1:1) and dried over magnesiumsulfate. Concentration under reduced pressure yields a residue of crudeo-(bromomethyl)phenylacetic acid. (Crystallization of the crude productfrom methylene chloride yields a product with melting point 130°-131° C.and a C:H ratio of 46.90:4.09). The crude o-(bromomethyl)phenylaceticacid, 400 ml of benzene and 38 g of triphenylphosphine is stirred at 80°C. for 5 hr and cooled and filtered to yield 57 g of title product,melting point 248°-249° C. The C:H:Br:P ratio is 66.22:4.94:16.16:6.49.

B. 3,4-Dinor-2,5-inter-o-phenylene-PGF₂α, 11,15-bis(tetrahydropyranylether), methyl ester (formula XXIII compound).

A mixture of 2.6 g of 57% sodium hydride in 100 ml of drydimethylsulfoxide at 66°-70° C. is slowly stirred under a nitrogenatmosphere for one hr. The resulting solution is then cooled to about15° C. and 15.2 g of the reaction product of Part A is added. Theresulting deep red mixture is then stirred at ambient temperature for 20hr and thereafter cooled to about 15° C. After cooling 6.6 g of3α,5α-dihydroxy-2β-(3α-hydroxy-trans-1-octenyl)-1.alpha.-cyclopentaneacetaldehyde, Υ-lactol, bis(tetrahydropyranyl ether) in 20 ml ofdimethylsulfoxide is added. The resulting mixture is then stirred atambient temperature for 2.5 hr, diluted with 6 ml of benzene, and shakenwith an ice cold solution of 15 g of potassium bisulfate in 300 ml ofwater and brine. Thereafter the resulting mixture is dried andconcentrated under reduced pressure to yield a residue which istriturated with a mixture of diethyl ether in Skellysolve-B.Concentration of the filtrate yields a residue which is thereaftertreated with excess ethereal diazomethane. After treatment with aceticacid the resulting organic solution is washed with cold dilute potassiumhydroxy, saturated brine, and dried. Concentration under reducedpressure yields a residue which is chromatographed on 2 kg of silicagel, eluting with 4 l of ethyl acetate in Skellysolve-B (1:1). Thereupon6.35 g of title product is obtained.

C. 2,5-Inter-o-phenylene-3,4-dinor-PGF₂α, methyl ester (formula XXIIIcompound).

A mixture of 1.6 g of the reaction product of Part B, 30 ml of aceticacid, 15 ml of water, and 3 ml of tetrahydrofuran is stirred at 40° C.for 4 hr and thereafter diluted with ethyl acetate (400 ml). Washing theresulting solution with a mixture of 30 ml of 50% sodium hydroxide and300 ml of ice and water, water, and saturated brine, yields a productwhich is concentrated under reduced pressure to a residue. The residueis then chromatographed on 200 g of silica gel, packed with ethylacetate (425 ml) and methanol 20 ml). Eluting with 5% methanol in ethylacetate yields 0.51 g of title product. Characteristic NMR absorptionsare observed at 7.1-7.5, 5.7-6.8, 5.33-5.6, and 3.62δ. The mass spectrumof the trimethylsilyl derivative yields a high resolution molecular ionat 632.3778.

D. 2,5-Inter-o-phenylene-3,4-dinor-5-iodo-6β-PGI₁, methyl ester and2,5-inter-o-phenylene-3,4-dinor-5,9α-epoxy-9-deoxy-6-iodo-PGF₁, methylester (formula XXIV and XXV compounds, respectively).

To a solution of 4.8 g of the reaction product of Part B and 100 ml ofmethylene chloride is added 100 ml of saturated sodium bicarbonate. Theresulting mixture is then stirred and cooled in an ice bath and asolution containing 4 g of iodine and 200 ml of dichloromethane is addedslowly over about 30 min. The resulting mixture is then stirred for 90min in a cooling bath and thereafter for 165 min at ambient temperature.Thereafter the resulting mixture is then diluted with ethyl acetate andwashed with 5% sodium sulfite and brine (200 ml). After drying oversodium sulfate, concentration under reduced pressure yields 5.3 g of adark brown oil. After dissolution of the oil in 80 ml of an aceticacid-water-tetrahydrofuran mixture (20:10:3) and stirring at 40°-45° C.for 3.5 hr, the resulting mixture is diluted with 800 ml of ethylacetate and washed with 800 ml of cold 5% sodium hydroxide, 400 ml ofwater, and 400 ml of brine. Drying over sodium sulfite and concentrationunder reduced pressure yields 4.15 g of an oil. Dissolution of the oilin 20 ml of dichloromethane and chromatography over 200 g of silica geleluting with 25-40% acetone in dichloromethane yields the mixture oftitle products. TLC R_(f) is 0.23 in 30% acetone in dichloromethane and0.25 and 0.30 in ethyl acetate. The mass spectrum for the trimethylsilylderivative exhibits a high resolution peak at 686.2309. NMR absorptionsare observed at 7.04-7.44, 5.0-5.73, 3.4-5.0, 3.62, 0.6-3.4, and0.6-1.03δ.

The mixture of title products contained above may be separated into twofractions (fraction I and fraction II) by the following technique:

The reaction product of Part B (0.50 g) in 25 ml of dichloromethane and25 ml of saturated aqueous sodium bicarbonate is treated with 0.5 ml ofiodine. After stirring in ice water for 90 min, the reaction mixture isdiluted with diethyl ether, washed with 10% aqueous sodium sulfite (105ml) and water (35 ml) and the organic filtrate dried over sodiumsulfate. Concentration under reduced pressure to an oil yields a mixtureof fractions I and II which are separated on silica gel by the elutionof 121 25 ml fractions as follows: 5% Skellysolve B in ethyl acetate(fractions 1-65), ethyl acetate (fractions 66-90), and acetone(fractions 91-121). For fraction I silica gel TLC R_(f) is 0.49 in 5%methanol in ethyl acetate. Fraction II exhibits silica gel TLC R_(f)0.44 in 5% methanol and ethyl acetate. For fraction I the mass spectrumof the trimethylsilyl derivative exhibits a weak molecular ion at 686and a high resolution peak at 615.1443. For fraction II the massspectrum of the trimethylsilyl derivative exhibits a high resolutionpeak at 615.1437. NMR absorptions in deuterochloroform for fraction Iare observed at 7.28, 5.60, 5.27, 4.65-3.80, 3.80, 3.69, and 2.70-1.11δ.For fraction II NMR absorptions in deuterochloroform are observed at7.25, 5.55, 5.30, 4.72-3.90, 3.80, 3.69, 3.66, 2.85-1.11 and 0.90δ.

E. Following the procedure of Part D, but omitting the treatment withacetic acid-water-tetrahydrofuran, the reaction product of Part C isconverted to a mixture of the title products of Part D.

F. 2,5-Inter-o-phenylene-3,4-dinor-5,9α-epoxy-9-deoxy-PGF₁, methyl ester(formula XXVIII) and 2,5-inter-o-phenylene-3,4-dinor-6β-PGI₁, methylester (formula XXVI).

Nitrogen is bubbled through a solution of 70 mg of the Fraction Iproduct of Part D in 6 ml of methanol for 2-3 min. Thereafter tributyltin chloride is added dropwise (about 7 drops), while continuingnitrogen bubbling for an additional 2-3 min thereafter. The resultingsolution is then stirred under an atmosphere of nitrogen and 70 mg ofsodium borohydride is added over 5-10 min. The resulting mixture is thenstirred at ambient temperature for about 45 min and thereafter dilutedwith 45 ml of brine and extracted with ethyl acetate (150 ml). Thecombined ethyl acetate extracts are then washed with brine (25 ml) anddried over sodium sulfate. Removal of solvent under reduced pressureyields a mixture of crude title products which is dissolved in 2 ml. ofethyl acetate and chromatographed on silica gel. Eluting with 1%methanol in ethyl acetate yields 25 mg of the formula XXVIII compoundand 11 mg of the formula XXVI compound.

For 2,5-inter-o-phenylene-3,4-dinor-5,9α-epoxy-9-deoxy-PGF₁, methylester, silica gel TLC R_(f) is 0.45 in 5% methanol and ethyl acetate.The mass spectrum for the trimethylsilyl derivative exhibits a highresolution peak at 560.3319. NMR absorptions are observed at 7.25, 5.50,5.1, 4.3-3.30, 3.78, 3.68, 2.75-1.10 and 0.90δ (deuterochloroformsolvent).

For 2,5-inter-o-phenylene-3,4-dinor-PGI₁, methyl ester, silica gel TLCR_(f) is 0.40 in 5% methanol and ethyl acetate. The mass spectrum of thetrimethylsilyl derivative exhibits a high resolution peak at 560.3319.NMR absorptions are observed at 7.25, 5.50, 4.6-3.75, 3.71, 3.67, 2.80,2.75-1.10, and 0.90δ (deuterochloroform solvent).

Alternatively, the fraction II product of Part D (70 mg) is employed inthe preparation of the formula XXVI and formula XXVII compounds asfollows:

The fraction II product of Part D (70 mg) in 3 ml of methanol is treatedwith 7 drops of tributyltin and 70 mg of sodium borohydride for 1.5 hrat ambient temperature. After product workup as above, the mixture ofcrude product is dissolved in 2 ml of dichloromethane andchromatographed over 10 g of silica gel eluting with 15-100% acetone indichloromethane.

For 2,5-inter-o-phenylene-3,4-dinor-5,9α-epoxy-9-deoxy-PGF₁, methylester, silica gel TLC R_(f) is 0.48 in 5% methanol in ethyl acetate. Themass spectrum for the trimethylsilyl derivative exhibits a weakmolecular ion at 560 and a high resolution peak at 489.2504. NMRabsorptions in deuterochloroform are observed at 7.25, 5.50, 4.45, 4.05,3.65, 3.66, 2.80-1.0, and 0.90δ.

G.2,5-Inter-o-phenylene-3,4-dinor-5,9α-epoxy-9-deoxy-6,7-didehydro-PGI₁,methyl ester (formula XXVII).

To a solution of 1.0 g of the reaction product of Part D (Fraction II)in 60 ml of toluene is added 3 ml of DBN. The resulting mixture is thenstirred at 40°-45° C. for 70 hr. During this time, the reaction mixtureis protected from contamination by atmospheric moisture by means of adrying tube. Thereafter an additional 2 ml of DBN is added and stirringand heating are continued for 26 hr. Thereafter the reaction temperatureis raised to 80° C. for 4 hr. The reaction at this time being complete,the reaction mixture is cooled, diluted with 50 ml of toluene, andwashed with 60 ml of ice water. The water washes are then combined andextracted with 60 ml of diethyl ether and the ethereal extracts arewashed with 30 ml of ice water and combined with the toluene solution.After drying of the organic solution over sodium sulfate and evaporationunder reduced pressure, a yellow oil (0.50 g) is obtained.Chromatography of the oil on 35 g of silica gel packed with 50% ethylacetate in Skellysolve-B and eluted with 50-100% ethyl acetate inSkellysolve-B yields 0.41 g of title product. Silica gel TLC R_(f) is0.24 in 30% acetone in methylene chloride and 0.28 in ethyl acetate. Themass spectrum of the trimethylsilyl derivative exhibits a highresolution peak at 558.3238. The infrared absorptions are observed at3380, 1740, 1650, 1495, 1435, 1335, 1295, 1260, 1100, 1055, 1015, 965,and 775 cm⁻¹. NMR absorptions are observed at 7.13-7.45, 5.84,5.46-5.71, 5.12-5.30, 3.5-4.34, 3.65, 2.98, 0.67-2.77, and 0.88δ.

H.2,5-Inter-o-phenylene-3,4-dinor-5,9α-epoxy-9-deoxy-6,7-didehydro-PGF₁.

A solution containing 0.11 g of the reaction product of Part G in 2 mlof methanol is diluted with 1 ml of water and 0.10 g of solid sodiumcarbonate. The resulting mixture is then stirred at ambient temperaturefor about 19 hr. The resulting mixture is then filtered withdiatomaceous earth and a precipitate washed with 10 ml of methanol. Thefiltrate is then concentrated under reduced pressure until the methanolhas been removed and then acidified with 1 ml of 1 N potassiumbisulfate. The resulting mixture is then diluted with 10 ml of brine andextracted with 45 ml of ethyl acetate. The organic extracts are thenwashed with brine, back-washed with ethyl acetate and the organicfractions combined, dried over sodium sulfate and concentrated underreduced pressure. The resulting residue, yellow oil (0.10 g), is thendissolved in 1 ml of 10% acetone in dichloromethane and chromatographedover 10 g of acid washed silica gel packed with 10% acetone indichloromethane. Eluting with 10-40% acetone in dichloromethane yields56 mg of title product. Silica gel TLC R_(f) is 0.20 in acetone,dichloromethane, acetic acid (30:70:2). The mass spectrum for thetrimethylsilyl derivative exhibits a high resolution peak at 616.3457.NMR absorptions are observed at 7.26, 5.73-6.19, 5.37-5.73, 5.04-5.27,3.33-4.33, 0.67-2.83, and 0.87δ.

I. 2,5-Inter-o-phenylene-3,4-dinor-5,9α-epoxy-9-deoxy-PGF₁.

The formula XXVIII reaction product of Part F (100 mg) and 3 ml ofmethanol is cooled and stirred in an ice bath under nitrogen atmosphere.Addition of 3 N aqueous potassium hydroxide (2 ml) is followed bystirring in a cooling bath under a nitrogen atmosphere for 5 min. Afterallowing the reaction mixture to warm to ambient temperature (stirringfor about 45 min), the resulting mixture is then diluted with 8 ml ofpotassium bisulfate, 5 ml of brine and sodium chloride. Extraction withethyl acetate (45 ml), washing with brine (30 ml), drying over sodiumsulfate, concentrating to a residue, and dissolving the residue indichloromethane (3 ml), chromatographing on 10 g of acid-washed silicagel, packed with 20% acetone in dichloromethane and eluting with 20-30%acetone in dichloromethane yields 53 mg of pure title product. Silicagel TLC R_(f) is 0.22 in 30% acetone and dichloromethane. The massspectrum exhibits a high resolution peak at 618.3570. NMR absorptions indeuterochloroform are observed at 7.28, 5.50, 3.62-4.67, 0.69-3.0, and0.87δ.

J. 2,5-Inter-o-phenylene-3,4-dinor-6β-PGI₁.

Following the procedure of Part I and chromatographing on 10 g of silicagel eluted with 30-40% acetone and dichloromethane yields from 100 mg ofthe formula XXVI product of Part F 80 mg of title product. Silica gelTLC R_(f) is 0.15 in 30% acetone in dichloromethane (2% acetic acidadded). The mass spectrum of the trimethylsilyl derivative exhibits ahigh resolution peak at 618.3564. NMR absorptions in deuterochloroformare observed at 7.25, 5.45, 4.55-3.75, 3.70, 2.90, 2.85-1.10 and 0.90δ.

Following the procedures described above in Example 1, there areprepared

2,5-inter-o-phenylene-3,4-dinor-PGF₂α, 11,15-bis(tetrahydropyranylethers),

2,5-inter-o-phenylene-3,4-dinor-PGF₂α compounds

2,5-inter-o-phenylene-3,4-dinor-5-iodo-PGI₁ compounds

2,5-inter-o-phenylene-3,4-dinor-5,9α-epoxy-9-deoxy-6-iodo-PGF₁ compounds

2,5-inter-o-phenylene-3,4-dinor-6β-PGI₁ compounds, and

2,5-inter-o-phenylene-3,4-dinor-5,9α-epoxy-9-deoxy-6,7-didehydro-PGF.sub.1compounds

in free acid or methyl ester form which exhibit the following side chainsubstituents:

15-Methyl-;

16-Methyl-;

15,16-Dimethyl-;

16,16-Dimethyl-;

16-Fluoro-;

15-Methyl-16-fluoro-;

16,16-Difluoro-;

15-Methyl-16,16-difluoro-;

17-Phenyl-18,19,20-trinor-;

17-(m-trifluoromethylphenyl)-18,19,20-trinor-;

17-(m-chlorophenyl)-18,19,20-trinor-;

17-(p-fluorophenyl)-18,19,20-trinor-;

16,16-Difluoro-;

15-Methyl-16,16-difluoro-;

17-Phenyl-18,19,20-trinor-;

17-(m-trifluoromethylphenyl)-18,19,20-trinor-;

17-(m-chlorophenyl)-18,19,20-trinor-;

17-(p-fluorophenyl)-18,19,20-trinor-;

15-Methyl-17-phenyl-18,19,20-trinor-;

16-Methyl-17-phenyl-18,19,20-trinor-;

16,16-Dimethyl-17-phenyl-18,19,20-trinor-;

16-Fluoro-17-phenyl-18,19,20-trinor-;

16,16-Difluoro-17-phenyl-18,19,20-trinor-;

16-Phenyl-17,18,19,20-tetranor-;

15-Methyl-16-phenyl-17,18,19,20-tetranor-;

16-(m-trifluoromethylphenyl)-17,18,19,20-tetranor-;

16-(m-chlorophenyl)-17,18,19,20-tetranor-;

16-(p-fluorophenyl)-17,18,19,20-tetranor-;

16-Phenyl-18,19,20-trinor-;

15-Methyl-16-phenyl-18,19,20-trinor-;

16-Methyl-16-phenyl-18,19,20-trinor-;

15,16-Dimethyl-16-phenyl-18,19,20-trinor-;

16-Phenoxy-17,18,19,20-tetranor-;

15-Methyl-16-phenoxy-17,18,19,20-tetranor-;

16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-;

16-(m-chlorophenoxy)-17,18,19,20-tetranor-;

16-(p-fluorophenoxy)-17,18,19,20-tetranor-;

16-Phenoxy-18,19,20-trinor-;

15-Methyl-16-phenoxy-18,19,20-trinor-;

16-Methyl-16-phenoxy-18,19,20-trinor-;

15,16-Dimethyl-16-phenoxy-18,19,20-trinor-;

13,14-Didehydro-;

16-Methyl-13,14-didehydro-;

16,16-Dimethyl-13,14-didehydro-;

16-Fluoro-13,14-didehydro-;

16,16-Difluoro-13,14-didehydro-;

17-Phenyl-18,19,20-trinor-13,14-didehydro-;

17-(m-trifluoromethylphenyl)-18,19,20-trinor-13,14-didehydro-;

17-(m-chlorophenyl)-18,19,20-trinor-13,14-didehydro-;

17-(p-fluorophenyl)-18,19,20-trinor-13,14-didehydro-;

16-Methyl-17-phenyl-18,19,20-trinor-13,14-didehydro-;

16,16-Dimethyl-17-phenyl-18,19,20-trinor-13,14-didehydro-;

16-Fluoro-17-phenyl-18,19,20-trinor-13,14-didehydro-;

16,16-Difluoro-17-phenyl-18,19,20-trinor-13,14-didehydro-;

16-Phenyl-17,18,19,20-tetranor-13,14-didehydro-;

16-(m-trifluoromethylphenyl)-17,18,19,20-tetranor-13,14-didehydro-;

16-(m-chlorophenyl)-17,18,19,20-tetranor-13,14-didehydro-;

16-Phenyl-18,19,20-trinor-13,14-didehydro-;

16-Methyl-16-phenyl-18,19,20-trinor-13,14-didehydro-;

16-Phenoxy-17,18,19,20-tetranor-13,14-didehydro-;

16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-13,14-didehydro-;

16-(m-chlorophenoxy)-17,18,19,20-tetranor-13,14-didehydro-;

16-Phenoxy-18,19,20-trinor-13,14-didehydro-;

16-Methyl-16-phenoxy-18,19,20-trinor-13,14-didehydro-;

13,14-Dihydro-;

16-Methyl-13,14-dihydro-;

16,16-Dimethyl-13,14-dihydro-;

16-Fluoro-13,14-dihydro-;

16,16-Difluoro-13,14-dihydro-;

17-Phenyl-18,19,20-trinor-13,14-dihydro-;

17-(m-trifluoromethylphenyl)-18,19,20-trinor-13,14-dihydro-;

17-(m-chlorophenyl)-18,19,20-trinor-13,14-dihydro-;

17-(p-fluorophenyl)-18,19,20-trinor-13,14-dihydro-;

16-Methyl-17-phenyl-18,19,20-trinor-13,14-dihydro-;

16,16-Dimethyl-17-phenyl-18,19,20-trinor-13,14-dihydro-;

16-Fluoro-17-phenyl-18,19,20-trinor-13,14-dihydro-;

16,16-Difluoro-17-phenyl-18,19,20-trionor-13,14-dihydro-;

16-Phenyl-17,18,19,20-tetranor-13,14-dihydro-;

16-(m-trifluoromethylphenyl)-17,18,19,20-tetranor-13,14-dihydro-;

16-(m-chlorophenyl)-17,18,19,20-tetranor-13,14-dihydro-;

16-(p-fluorophenyl)-17,18,19,20-tetranor-13,14-dihydro-;

16-Phenyl-18,19,20-trinor-13,14-dihydro-;

16-Methyl-16-phenyl-18,19,20-trinor-13,14-dihydro-;

16-Phenoxy-17,18,19,20-tetranor-13,14-dihydro-;

16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-13,14-dihydro-;

16-(m-chlorophenoxy)-17,18,19,20-tetranor-13,14-dihydro-;

16-(p-fluorophenoxy)-17,18,19,20-tetranor-13,14-dihydro-;

16-Phenoxy-18,19,20-trinor-13,14-dihydro-;

16-Methyl-16-phenoxy-18,19,20-trinor-13,14-dihydro-;

13-cis-;

16-Methyl-13-cis-;

16,16-Dimethyl-13-cis-;

16-Fluoro-13-cis-;

16,16-Difluoro-13-cis-;

17-Phenyl-18,19,20-trinor-13-cis-;

17-(m-trifluoromethylphenyl)-18,19,20-trinor-13-cis-;

17-(m-chlorophenyl)-18,19,20-trinor-13-cis-;

17-(p-fluorophenyl)-18,19,20-trinor-13-cis-;

16-Methyl-17-phenyl-18,19,20-trinor-13-cis-;

16,16-Dimethyl-17-phenyl-18,19,20-trinor-13-cis-;

16-Fluoro-17-phenyl-18,19,20-trinor-13-cis-;

16,16-Difluoro-17-phenyl-18,19,20-trinor-13-cis-;

16-Phenyl-17,18,19,20-tetranor-13-cis-;

16-(m-trifluoromethylphenyl)-17,18,19,20-tetranor-13-cis-;

EXAMPLE 2

2,5-Inter-o-phenylene-3,4-dinor-5,9α-epoxy-9-deoxy-6,7-didehydro-PGF.sub.1,sodium salt.

A solution of 383 mg of the reaction product of Example 1, Part H in 8.5ml of methanol under a nitrogen atmosphere are treated at 25° C. with asingle equivalent (8.8 ml) of 0.1 N sodium methoxide in methanol for 5hr. The resulting solution is then concentrated under reduced pressure(removing the methyl acetate byproduct), then redissolved in 8.5 ml ofmethanol and 1.5 ml of water. This solution is then stirred for 12 hrunder a nitrogen atmosphere whereupon 10 ml of water is added and themethanol removed under reduced pressure. The resulting aqueous solutionis then freeze-dried, yielding a residue of pure title product.

EXAMPLE 3

2,5-Inter-o-phenylene-3,4-dinor-5,9α-epoxy-9-deoxy-6,7-didehydro-PGF.sub.1,tris(hydroxymethyl)aminomethane salt and methyl ester.

The title product of Example 2 is acidified with dilute aqueoushydrochloric acid and quickly extracted from the aqueous solution withdiethyl ether. The ethereal solution is then combined with stirring witha solution of tris(hydroxymethyl)aminomethane, containing exactly 1equivalent of this base. The resulting aqueous solution, containing thetitle salt, is then purified in accordance with the isolation procedureof Example 2, thereby yielding pure title product.

The title product of Example 2 is dissolved in dimethylformamide (DMF)and thereafter there is added an equivalent of methyl iodide. Theresulting mixture is then maintained at ambient temperature withstirring for several hours, whereupon silica gel TLC analysis indicatesthe esterification reaction is complete. Thereafter, the reactionmixture is washed successively with water and brine and concentrated toa residue containing pure title methyl ester.

EXAMPLE 4

2,5-Inter-o-phenylene-3,4-dinor-5,9α-epoxy-9-deoxy-6,7-didehydro-PGF.sub.1,phenyl ester.

The title product of Example 2 is dissolved in dimethylformamide andthereafter an equivalent of N-methyl-2-bromopyridium iodide is addedwith stirring. After several hours, the resulting mixture is combinedwith one equivalent of phenol in triethylamine and the resulting mixtureis maintained at ambient temperature with stirring for several hours.When silica gel TLC analysis indicates the esterification reaction iscomplete, pure title ester is obtained by purification.

EXAMPLE 5

2,5-Inter-o-phenylene-3,4,17,18,19,20-hexanor-5,9α-epoxy-9-deoxy-6,7-didehydro-16-phenoxy-PGF₁and its methyl ester.

Following the procedure of Example 1, Parts B and C,3α,5α-dihydroxy-2γ-(3α-hydroxy-4-phenoxy-trans-1-butenyl)-1α-cyclopentaneacetaldehyde,γ-lactol, bis(tetrahydropyranyl ether), 5.4 g, is transformed to 3.97 gof 2,5-inter-o-phenylene-16-phenoxy-3,4,17,18,19,20-hexanor-PGF₂α,methyl ester. Following the procedure of Example D of Part 1, thepreceding compound is transformed to2,5-inter-o-phenylene-16-phenoxy-3,4,17,18,19,20-hexanor-5,9α-epoxy-9-deoxy-6-iodo-PGF₁,methyl ester, 1.29 g. The mass spectrum for the trimethylsilylderivative exhibits a weak molecular ion at 722, a demethylated highresolution peak at 707.1747 and other peaks at 682, 615, 594, 561, 525,487, and 397. Characteristic infrared absorptions are observed at 3360,1735, 1600, 1585, 1495, 1245, 1080, 1040, 1020, 970, 755, and 690 cm⁻¹.

The preceding reaction product (0.25 g) is then dehydroiodinatedaccording to the procedure of Example 1, Part F, yielding2,5-inter-o-phenylene-16-phenoxy-3,4,17,18,19,20-hexanor-5,9α-epoxy-9-deoxy-6,7-didehydro-PGF₁,methyl ester (90 mg) as a colorless oil. The mass spectrum for thetrimethylsilyl derivative exhibits a high resolution peak at 594.2832and other peaks at 579, 563, 504, 500, 487, 473, 469, 414, 397, 379, and243. Hydrolysis of the 200 mg sample of the above methyl ester yields110 mg of the corresponding acid,2,5-inter-o-phenylene-16-phenylene-3,4,17,18,19,20-hexanor5,9α-epoxy-9-deoxy-6,7-didehydro-PGF₁. The mass spectrum for thetrimethylsilyl derivative exhibits a high resolution peak at 652.3045and other peaks at 637, 562, 545, 455, 437, 365, and 243.

EXAMPLE 6

2,5-Inter-o-phenylene-3,4-dinor-16,16-difluoro-5,9α-epoxy-9-deoxy-6,7-didehydro-PGF₁and its methyl ester.

Following the procedure described in Example 5, there are successivelyprepared from3α,5α-dihydroxy-2β-(3α-hydroxy-4,4-difluoro-trans-1-octenyl)-1α-cyclopentaneacetaldehyde,γ-lactol, 11,15-bis(tetrahydropyranyl ether), (4.8 g), the followingproducts:

(a) 2,5-inter-o-phenylene-3,4-dinor-16,16-difluoro-PGF₂α,11,15-bis(tetrahydropyranyl ether), methyl ester, 5.)4 g as a yellowoil; the mass spectrum for the trimethylsilyl derivative exhibiting aweak molecular ion at 722 and a high resolution peak at 707.1888;

(b)2,5-inter-o-phenylene-3,4-dinor-16,16-difluoro-5,9α-epoxy-9-deoxy-6-iodo-PGF₁,methyl ester, 1.64 g from 4.0 g of the reactant of Part (a);

(c)2,5-inter-o-phenylene-3,4-dinor-16,16-difluoro-5,9α-epoxy-9-deoxy-6,7-didehydro-PGF₁,methyl ester, 70 mg from 250 mg of the reactant of Part (b); the massspectrum for the trimethylsilyl derivative exhibiting a high resolutionpeak of 594.2292 and other peaks at 579, 563, 521, 504, 487, 414, 397,and 243;

(d)2,5-inter-o-phenylene-3,4-dinor-16,16-difluoro-5,9α-epoxy-9-deoxy-6,7-didehydro-PGF₁,320 mg from 520 mg of the reactant of Part (c); the mass spectrum forthe trimethylsilyl derivative exhibits a high resolution peak at652.3240.

EXAMPLE 7

2,5-Inter-o-phenylene-3,4-dinor-16,16-dimethyl-5,9α-epoxy-9-deoxy-6,7-didehydro-PGF₁,methyl ester.

Following the procedure described in Example 1, there are successivelyprepared from3α,5α-dihydroxy-2β-(3α-hydroxy-4,4-dimethyl-trans-1-octenyl)-1α-cyclopentaneacetaldehyde,γ-lactol, 11,15-bis(tetrahydropyranyl ether), the following products;

(a) 2,5-inter-o-phenylene-3,4-dinor-16,16-dimethyl-PGF₂α,11,15-bis(tetrahydropyranyl ether), methyl ester;

(b)2,5-inter-o-phenylene-3,4-dinor-16,16-dimethyl-5,9α-epoxy-9-deoxy-6-iodo-PGF₁,methyl ester, 1.08 g from 2.4 g of the reactant of Part (a). Silica gelTLC R_(f) is 0.33 in 30% acetone and dichloromethane. The mass spectrumof the trimethylsilyl derivative exhibits a weak molecular ion at 714and a high resolution peak at 699.2371. Infrared absorptions areobserved at 3424, 1737, 1607, 1495, 1258, 1189, 1155, 1101, 1069, 1045,1017, 971, and 758 cm⁻¹.

(c)2,5-inter-o-phenylene-3,4-dinor-16,16-dimethyl-5,9α-epoxy-9-deoxy-6,7-didehydro-PGF₁,methyl ester, 0.32 g from 1.0 g of the reactant of Part (b); the massspectrum for the trimethylsilyl derivative exhibiting a high resolutionpeak at 571.3287. Silica gel TLC R_(f) is 0.34 in 30% acetone anddichloromethane. NMR absorptions are observed at 7.3, 5.90, 5.60, 5.20,4.20, 4.00-3.50, 3.67, 2.90, 2.80-1.10, 0.90, and 0.88δ(deuterochloroform solvent).

EXAMPLE 8

2,5-Inter-o-phenylene-3,4-dinor-5,9α-epoxy-9-deoxy-6,7-didehydro-PGF.sub.1,sec-butyl ester.

To a stirred solution of 0.16 g of the reaction product of Example 1,Part G, in 5 ml of methylene chloride is added 0.07 g of triethylamineand 55 mg of isobutyl chloroformate. The solution is stirred for 30 minat ambient temperature (protected from moisture by a drying tube).Thereafter 55 mg of p-hydroxyacetophenone is added and stirring iscontinued at ambient temperature for 90 min. Elution of the resultingmixture with 30 ml of dichloromethane followed by washing with 10 ml ofwater, 10 ml of 0.1 N aqueous sodium hydroxide and 15 ml of water yieldsa solution which is dried over sodium sulfate and concentrated underreduced pressure to a residue. Dissolving the residue in 3 ml ofdichloromethane and chromatographing over 20 g of acid-washed silicagel, eluting with 5-30% acetone in dichloromethane yields pure titleproduct (0.10 g). Silica gel TLC R_(f) is 0.53 in 30% acetone anddichloromethane (2% acetic acid added). The mass spectrum of thetrimethylsilyl derivative exhibits a high resolution peak at 600. NMRabsorptions in deuterochloroform are observed at 7.27, 5.84, 5.4-5.75,5.15-5.4, 3.55-4.34, 0.90, and 0.79δ. ##STR2##

We claim:
 1. A prostacyclin intermediate of formula VIIIwherein R₂₈ is--OR₁₀, --CH₂ OR₁₀, hydroxy, hydroxymethyl, or hydrogen, wherein R₁₀ isa blocking group removable by mild acidic hydrolysis; wherein Y₁ is (1)trans-CH═CH--, (2) cis-CH═CH--, (3) --CH₂ CH₂ --, or (4)--C.tbd.C--,wherein M₈ is α-R₅ :β-OR₁₀ or α-OR₁₀ :β-R₅, wherein R₅ ishydrogen or methyl and R₁₀ is as defined above, or α-R₅ :β-OH orα-OH:β-R₅, wherein R₅ is as defined above; wherein L₁ is α-R₃ :β-R₄,α-R₄ :β-R₃, or a mixture of α-R₃ :β-R₄ and α-R₄ :β-R₃, wherein R₃ and R₄are hydrogen, methyl, or fluoro, being the same or different, with theproviso that one of R₃ and R₄ is fluoro only when the other is hydrogenor fluoro: wherein R₇ is (1) --(CH₂)_(m) --CH₃, wherein m is an integerfrom one to 5, inclusive; (2) phenoxy; (3) phenoxy substituted by one, 2or 3 chloro, fluoro, trifluoromethyl, alkyl of one to 3 carbon atoms,inclusive, or alkoxy of one to 3 carbon atoms, inclusive, with theproviso that not more than two substituents are other than alkyl; (4)phenyl; (5) phenyl substituted by one, 2 or 3 chloro, fluoro,trifluoromethyl, alkyl of one to 3 carbon atoms, inclusive, or alkoxy ofone to 3 carbon atoms, inclusive, with the proviso that not more thantwo substituents are other than alkyl; (6) phenylmethyl, phenylethyl, orphenylpropyl; or (7) phenylmethyl, phenylethyl, or phenylpropylsubstituted by one, 2 or 3 chloro, fluoro, trifluoromethyl, alkyl of oneto 3 carbon atoms, inclusive, or alkoxy of one to 3 carbon atoms,inclusive, with the proviso that not more than two substituents areother than alkyl; with the proviso that R₇ is phenoxy or substitutedphenoxy, only when R₃ and R₄ are hydrogen or methyl, being the same ordifferent;wherein R₁ is (1) hydrogen; (2) alkyl of one to 12 carbonatoms, inclusive; (3) cycloalkyl of 3 to 10 carbon atoms, inclusive; (4)aralkyl of 7 to 12 carbon atoms, inclusive; (5) phenyl; (6) phenylsubstituted with one, 2 or 3 chloro or alkyl of one to 3 carbon atoms;(7) phenyl substituted in the para position by(a) --NH--CO--R₂₅ (b)--CO--R₂₆ (c) --O--CO--R₂₇ (d) --CH═N--NH--CO--NH₂ wherein R₂₅ ismethyl, phenyl, acetamidophenyl, benzamidophenyl, or --NH₂ ; R₂₆ ishydroxy, methyl, phenyl, --NH₂, or methoxy; and R₂₇ is phenyl oracetamidophenyl, inclusive, or a pharmacologically acceptable saltthereof when R₁ is hydrogen.